# Versatility of Stenotrophomonas maltophilia: Ecological roles of RND efflux pumps

Amandine Chauviat, Thibault Meyer, Sabine Favre-Bonté

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Amandine Chauviat, Thibault Meyer, Sabine Favre-Bonté. Versatility of Stenotrophomonas maltophilia: Ecological roles of RND efflux pumps. Heliyon, 2023, 9 (4), pp.e14639. 10.1016/j.heliyon.2023.e14639. hal-04085782

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Review article

# Versatility of *Stenotrophomonas maltophilia*: Ecological roles of RND efflux pumps

Amandine Chauviat, Thibault Meyer<fnref n="1" />, Sabine Favre-Bonté<fnref n="1" />, *

<figure><img src="image_2.png" /></figure>

Université de Lyon, Université Claude Bernard Lyon 1, UMR CNRS 5557, UMR INRAe 1418, VetAgro Sup, Ecologie Microbienne, F-69622

Villeurbanne, France

ARTICLE INFO

Keywords:

Environmental resistance

Opportunistic pathogen

Ecological niche

Natural inducer

Regulatory pathway

A B S T R A C T

S. maltophilia is a widely distributed bacterium found in natural, anthropized and clinical envi-
ronments. The genome of this opportunistic pathogen of environmental origin includes a large
number of genes encoding RND efflux pumps independently of the clinical or environmental
origin of the strains. These pumps have been historically associated with the uptake of antibiotics
and clinically relevant molecules because they confer resistance to many antibiotics. However,
considering the environmental origin of S. maltophilia, the ecological role of these pumps needs to
be clarified. RND efflux systems are highly conserved within bacteria and encountered both in
pathogenic and non-pathogenic species. Moreover, their evolutionary origin, conservation and
multiple copies in bacterial genomes suggest a primordial role in cellular functions and envi-
ronmental adaptation. This review is aimed at elucidating the ecological role of S. maltophilia
RND efflux pumps in the environmental context and providing an exhaustive description of the
environmental niches of S. maltophilia. By looking at the substrates and functions of the pumps,
we propose different involvements and roles according to the adaptation of the bacterium to
various niches. We highlight that i) regulatory mechanisms and inducer molecules help to un-
derstand the conditions leading to their expression, and ii) association and functional redun-
dancy of RND pumps and other efflux systems demonstrate their complex role within
S. maltophilia cells. These observations emphasize that RND efflux pumps play a role in the
versatility of S. maltophilia.

1. Introduction

*Stenotrophomonas maltophilia* is a Gram-negative, aerobic, ubiquitous, non-fermentative rod-shaped bacterium belonging to the class of Gammaproteobacteria. It is found in various natural and anthropogenic environments, e.g. soil, water, sediment, or in association with plants [1]. Its presence in association with invertebrates is documented, but less described. *S. maltophilia* is also found in clinical settings where it can cause a wide variety of infections [2]. The different types of infection it can cause are well described, and so is its prevalence in the hospital environment [3,4]. This opportunistic pathogen has a low virulence but is of particular interest due to its natural and intrinsic antibiotic resistance phenotype [5,6]. The multidrug resistant (MDR) phenotype is encountered among

<footnote>* Corresponding author.</footnote>

<footnote>E-mail addresses: achauvia@gmail.com (A. Chauviat), thibault.meyer@univ-lyon1.fr (T. Meyer), sabine.favre-bonte@univ-lyon1.fr (S. Favre-Bonté).</footnote>

<footnote n="1">¹ SFB and TM contributed equally to the supervision of this article. Author order was determined on the basis of seniority.</footnote>
clinical strains. It is an issue when it comes to treating infections because it reduces the scope of effective antibiotics. Nonetheless,
strains from non-clinical environments may also display this phenotype [7]. Selective pressure from antibiotics is generally low in
these environments and variable between countries [8,9], and cannot alone explain the presence of the MDR phenotype. The
phenotype is due to cumulated antibiotic resistance mechanisms such as low permeability, production of antibiotic-modifying en-
zymes or efflux systems.

S. maltophilia possesses several antibiotic resistance mechanisms contributing to the MDR phenotype, e.g. L1 and L2 β-lactamases, aminoglycoside-modifying enzymes, SmQnr, a DNA gyrase- and topoisomerase-protecting enzyme, and low membrane permeability [6]. However, efflux systems are the main cause of antibiotic resistance in this species [10,11]. The genome of S. maltophilia displays two ATP-binding cassette (ABC) pumps (SmrA and MacABCsm), two Major Facilitator family (MFS) pumps (MfsA and EmrCAB), and eight Resistance Nodulation Division (RND) pumps (belonging to the Sme family) that contribute to their resistance to antibiotics [4, 12–14].

RND efflux pumps are specific to Gram-negative bacteria: they are located across the two membranes of the bacterial envelope, and extrude molecules from the cytoplasm or the periplasm directly outside the bacterial cell [15]. These chromosomally encoded pumps are primarily studied in a clinical context for their role in the emergence of antibiotic resistance. However, they can manage a wider spectrum of molecules than antibiotics and extrude other toxic and non-toxic compounds of natural and synthetic origin [10,16–18]. Given the wide distribution of S. maltophilia in extremely diverse environments, it is exposed to molecules of diverse natures, and this requires high adaptability. Moreover, the MDR phenotype is independent of the living conditions of bacteria [6,19], and no difference between the genomic contents of clinical and environmental isolates has been noticed [14,20,21]. At the phylogenetic level, while the S. maltophilia species complex is divided into 5 genospecies (namely S. maltophilia sensu lato and Sgn1 – 4) with some enriched in clinical or environmental strains, none of them is specific to a clinical or environmental origin as each group consists of a mixture of strains of both origins [22]. The presence of eight RND pumps in both clinical and environmental strains [14] and their broad range of substrates support the idea that they are involved in the adaptation of the species to various niches and contribute to its versatile nature [1]. Therefore, RND systems play different roles and have different functions in non-clinical environments where they contribute to the physiology of the bacterium and to its ability to interact with other organisms [6]. Understanding the fine-tuned regulation of these systems is one of the keys to better grasp the conditions of their expression and better define their ecological role.

In this review, we accurately present the distribution of S. maltophilia across the wide variety of non-clinical environments it colonizes. Then, we focus on the roles that RND efflux pumps may play in the physiology of the bacterium and its adaptation to various stresses. In order to highlight the complexity of the association of S. maltophilia RND pumps – the so-called Sme pumps– we describe their genetic organization. Finally, we describe the conditions under which these pumps are expressed by investigating their regulation mechanisms and the inducing molecules.

## 2. *S. maltophilia*: a widely distributed species

S. maltophilia can be isolated from diverse natural and anthropized environments. Its presence in clinical settings is well known and well documented due to the health hazard it represents [3,4], but to our knowledge the diversity of the natural or anthropized environmental habitats it colonizes has not been reviewed recently [1]. This is why we propose an overview of the different ecological niches where S. maltophilia has been found.

### 2.1. Environments

#### 2.1.1. Soils

S. maltophilia is found in various soils around the globe [14,20,23-33]. Its presence has been established in soils polluted with various types of contaminant like heavy metals and antibiotics [14,34], heavy metals from a mine [35], metals and industrial minerals from a mineral mining site [36]. It has also been found in soil from a gold mine [37], and soils polluted with zinc and lead from waste heaps [38], cadmium and chromium [39,40] and copper [41]. It has been recovered in crude oil-, transformer oil- and sulfurous oil-contaminated soils [42-46], fuel-, diesel-, gasoline-, hydrocarbon-, and oil-contaminated soils [47-51], and chemical factory-contaminated soil [52]. S. maltophilia has even been isolated from a nitroaromatic-contaminated site [53], TNT-contaminated soil [54], soils heavily contaminated with the explosive hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) [55], polycyclic aromatic hydrocarbons (PAHs), and pentachlorophenol (PCP) [49,56,57], and decabromodiphenyl ether- (BDE209-) and tetrabromobisphenol A-(TBBPA-) contaminated soils [58]. It has been found in soils containing industrial wine waste [59], pesticide and alkylphenol poly-ethoxylate surfactants [60,61], an E-waste dismantling area [62] or even plastic debris [63].

S. maltophilia has been found in soils where the presence of a contaminant is not specified, including bulk soil [64], nonvegetated dunes of the Merzouga desert [65], drought-prone ecosystems [66], beach sand [67], soil from an island [68], soil from the banks of a river [69], permafrost soil [70], soil nearby a glacier [71], slushy soil [72] and slaughterhouse soil [73].

It is present in soils associated with agricultural land use such as farmed and amended soils, but also in amendments [7,14,74-79]. It has been found in horse compost, cattle manure, and horse manure [80], in soil from a poultry farm [81,82] and a ranch [83], in farm surface soil [84], in different plantation areas [24], in soils from vegetable, rice [85], wheat, and corn fields [86-89], from fields where crops suffered from diseases caused by nematodes [90] and from a sugarcane plantation [91]. S. maltophilia was even detected in a nutrient solution of a culture medium in a hydroponics farm [92].
### 2.1.2. Water, waterborne environments, sediment

S. maltophilia has been identified in water, aquatic environments, and sediment its presence has been demonstrated in diverse natural water environments like rivers [93], sediment and water of rivers and streams [94] and cenotes [95], at the surface of a lake [96], in dripping water from a cave [97], marshwater [67], seawater [98–102], polluted coastal water [103], groundwater [104,105] and biofilms in natural and artificial aquifers [106].

S. maltophilia has been isolated in association with wastewater and water treatment plants, in surface water, groundwater, and bioremediation reactor samples from the Niagara watershed [107], water treatment and subsequent distribution systems [108], a drinking-water treatment plant [109], wastewater treatment plants [110], treated wastewater effluents [111], palm oil mill effluents [112], the final effluents of a pig farm [113], wastewater from a petroleum reservoir [114], and in contaminated sewage [44].

Several types of sediment containing S. maltophilia have been identified, i.e. seleniferous agricultural drainage pond sediment [115], anaerobic and activated sludge from a wastewater treatment plant [39,116–119], wastewater bioreactor sludge [120], wastewater sediment in a date-processing unit [121], sediment from a storage facility for coal tailings solids [122], coastal sediment of a shipbreaking yard [123], sediment from a canal [124], freshwater [125], seawater [100,102] and polluted river [126] sediments, and even microplastics from a river [127].

## 2.2. Interaction with eukaryotes

### 2.2.1. Plants

S. maltophilia interacts with diverse plants, notably in the rhizosphere. It has been isolated from the rhizospheres of plants growing in a landfill [128], of oilseed rape (Brassica napus subsp. napus and oleifera) and shepherd's purse (Capsella bursa-pastoris) [129,130], sorghum (Sorghum bicolor) [131,132], rice (Oryza sativa) [133], oat (Avena sativa), and ribwort plantain (Plantago lanceolata) [41], crops [134,135], cabbage (Brassica oleracea), mustard (Sinapis alba), corn (Triticum vulgare), beet (Beta vulgaris) [136,137], potato (Solanum tuberosum) [138,139], tomato (Solanum lycopersicum) plants [66], eggplant (Solanum melongena) [140], strawberry (Fragaria x ananassa) [141], alfalfa (Medicago sativa), and lamb's quarter (Chenopodium album) [142,143]. The rhizospheres of barnyard grass (Echinochloa crus-galli), corn spurrey (Spergula arvensis), goldenrod (Sonchus sp.), Italian ryegrass (Lolium multiflorum), quackgrass (Elymus repens) [143], butternut (Cucurbita moschata) [144] and silver-leafed milkvetch (Astragalus bisulcatus) [145] can also be colonized by S. maltophilia. It has been collected from the rhizosphere of lettuce [88], maize (Zea mays subsp. mays) [146,147], sunflower (Helianthus annuus) [148], and eucalyptus (Eucalyptus spp.) [149]. Strains have been recovered from wet brown forest soil [150], grassland soil [151,152], and from the rhizospheres of Bermuda grass (Cynodon dactylon), St. Augustine grass (Stenotaphrum secundatum), pasture grass, Bahais grass, Heliconia, palm grove, wheat (Triticum sp.), barley (Hordeum vulgare) [64], and silver-leafed milkvetch (Astragalus bisulcatus) [145].

S. maltophilia is part of the phyllosphere of green bean (Phaseolus vulgaris) [153], potato (Solanum tuberosum) [138,154], and rice (Oryza sativa) [155] and has been described as an epiphyte of common ivy (Hedera helix) [156] and white clover (Trifolium repens) leaves [38], and medicinal Cannabis flower [157]. It has been described as an endophyte of poplar (Populus sp.) [158], rice (Oryza sp.) seed and plant [159–161], potato (Solanum tuberosum) [162], white clover (Trifolium repens) leaves and nodules [38], common bean seeds and peanut (Arachis hypogea) nodules [75], sunflower (Helianthus sp.) roots [163], cactus (Euphorbia trigona) roots and stems [164], and rockfoil (Saxifraga stellaris var. alpigena) [165].

In addition, the surfaces of diverse fruits and vegetables are colonized by S. maltophilia. It has been found on grapes in Chilean vineyards [166], potatoes, lettuce [167,168], carrot and turnip [169], endive lettuce [170], and leafy green vegetables (sweet basil, kale, and parsley) [92].

### 2.2.2. Animals

S. maltophilia is associated with diverse animals. Whether it is part of the animal's microbiota, pathogenic or in transient association with the host is not always clearly specified, but details are given when available.

S. maltophilia is found in reptiles, e.g., in the oral microflora of snakes [171,172] and in prairie rattlesnakes [173]. It has been held responsible for chronic respiratory disease of the ball python [174] and for septicemia in the West African dwarf crocodile [175].

S. maltophilia has been isolated from mammals. It has been found in the feces of tapirs [176], in porcine semen [177], and can cause mastitis in cows [178], chronic respiratory disease in horses, cats, and dogs [174], hepatitis in buffalo [179] or abscesses in Oman goat [180]. It has been held responsible for the contamination of bovine embryos and semen during long-term preservation in liquid nitrogen [181].

S. maltophilia has been detected in association with fish including cultured yellowtail (Seriola quinqueradiata) [182], cultured channel catfish (Ictalurus punctatus) [183], in the kidneys of juvenile African catfish (Clarias gariepinus) [184], and in the spleen of rainbow trout (Oncorhynchus mykiss) [185] where it causes disease. It has also been found in gilt-head bream (Sparus aurata) suffering from Gill disease [186].

In birds, S. maltophilia has been recovered from feces in a poultry farm [81], from the environment of backyard poultry flocks [187], and from the microbiota of Condor gut [188].

The previously described presence of S. maltophilia in farm soil and effluents can be linked to its association with animals. A close relationship has been evidenced between the animal, its environment, its food, and the agricultural products aimed for human and/or animal consumption.

The association of S. maltophilia and invertebrates is underestimated and has never been recognized as a real important niche for S. maltophilia. However, its presence in association with invertebrates is highly documented. It has been found in the gut microbiota of
Hermetia illucens [189], the bark beetle (Ips typographus), and the Asiatic rhinoceros beetle (Oryctes rhinoceros) [190,191], *Ips sex-dentatus* [192] and cockroach (Blatta orientalis Linnaeus, 1758) [193], in organs and the hemolymph of the camel tick (*Hyalomma dromedarii*) [194] and in other tick species (*Ixodes ricinus*, *Dermacentor reticulatus*, *Haemaphysalis concinna*) [195,196]. It has been identified as an endophyte of the pine wood nematode (*Bursaphelenchus xylophilus*) [197,198], in association with the nematode *Steinernema* sp. [199], in the coelomic cavity of earthworms (*Eiseinia foetida*) in vermicompost [200], in the digestive track of flies (*Lutzomyia longipalpis*) [201], and on the exoskeleton of flies (*Pollenia rudis sensu stricto* Fabricius 1794) [202]. It has been collected from the gut of housefly (*Musca domestica*) larvae [203,204], in the moth fly (*Clogmia albipunctata*) [205], in macerated *Stomoxys calcitrans* larvae and their mucus [206], in the gut microbiotas of mosquitoes (*Aedes albopictus*, *Aedes aegypti*) [207], muga silkworms (*Antheraea assamensis*) [208], and tarantulas (*Chilobrachys guangxiensis*) [209], and in the hemolymph microbiota of honey bees (*Apis mellifera* and *Apis cerana*) [210]. The bacterium has also been detected in the microbiota and feces of different marine invertebrates including anemones (*Anemonia sulcata* and *Actinia equina*) and holothurians (*Holothuria tubulosa* and *Holothuria forskali*) [211], and deep-sea invertebrates – a sponge specimen of *Stelletta* sp. and an unidentified sponge, from sea urchin (*Echinodermata*) and a brittle star (*Ophiura ophiura*) specimens – [212], frozen Antarctic krill [213] and in the gut of shrimp [102]. It has been described as part of the microbiome of free-living amoebas [214–216], as an endophyte of the fungus *Zoophagus insidians* [217], and in soil under cypress agaricus (*Agaricus lilaceps*) [218].

The association of *S. maltophilia* with animals and invertebrates raises questions about their role as a reservoir and possible vector of the bacterium. Further studies aimed at characterizing the types of animal-bacterium interaction and the vectorial potential of animals would help to specify the compartments colonized by *S. maltophilia* and the role played by animals and invertebrates in its dissemination.

### 2.3. *S. maltophilia* at the interface of the environmental, animal, and human compartments: a One Health bacterial model

Owing to its huge environmental reservoir, *S. maltophilia* lies at the interface between the environment, animals, and humans. As an opportunistic and multiresistant pathogen, its wide occurrence represents a global health threat [219] and confirms the importance of considering its study within the framework of a One Health approach.

The presence of *S. maltophilia* in natural water bodies is described in section 2.1.2, but its presence is also extended to drinking water [220,221]. It was isolated in drinking water systems [222–227], in drinking water collected from domestic taps in an urban area [228], in microfiltered water dispensers [229], in edible ice and ice cubes [230,231] and in hospital sink and tap water [232,233].

*S. maltophilia* has been detected in human food, i.e. Albacore tuna and seabream [234,235], soaked cod products from salted and dried cod [236], beef muscle [237], poultry meat [238], milk and cheeses [239–247], ready-to-eat street food (spring rolls, cold noodles, fruit platters) [248] and quick-frozen boiled dumplings [249]. Isolates have been recovered from beverages like unpasteurized beer [250], bottled water [153,251], and soda fountain machine beverages [252]. *S. maltophilia* has notably been recognized as the causal agent of food spoilage [253]. As previously mentioned, it has been recovered from fruit and vegetables, so that it is part of the human and animal food chains.

*S. maltophilia* is present in domestic environments, more specifically in wet conditions. Isolates have been recovered from home air and dust [254], from contact lenses [255–257], dishwasher rubber seal [258], water, faucets, and sink drains [259], in a biofilm in a university fountain drain [260] and in a home-used nebulizer [261].

*S. maltophilia* is as described previously a widely distributed species in the environment, colonizing a wide variety of ecological niches. However, several important gaps in the knowledge of its ecology remain. In particular, its abundance and prevalence in different environments are two aspects that have been poorly studied [262] and the correlation between the presence of *S. maltophilia* and the presence of selection pressures has never been established. This knowledge would provide new insights into the versatile lifestyle of *S. maltophilia*.

## 3. Roles of *S. maltophilia* RND efflux pumps

We have just described the extremely varied natural and anthropogenic niches of *S. maltophilia* that make up its environmental reservoir. Its ability to colonize those diverse environments relies to some extent on its capacity to manage the huge variety of molecules to which it is exposed. Multidrug efflux systems, among which the RND superfamily, are part of the core genome of the species [12,14].

RND efflux systems are found in all three kingdoms of the living world [263] and have versatile conformations that enable them to bind to a wide variety of substrates [16]. These tripartite systems are composed of a transporter – the inner membrane protein (IMP) also called RND protein or RND transporter –, a periplasmic adaptor – the membrane fusion protein (MFP) –, and a multidrug exporter – the outer membrane protein (OMP). The IMP recognizes its substrate in the periplasm or the cytoplasm depending on the hydrophobicity of the molecule [15], and the substrate is directly exported outside the cell *via* the OMP channel. The whole process draws the energy needed to export the compounds from the proton motive force [264].

In bacteria, RND efflux pumps are essentially known and studied for antibiotic and heavy metal extrusion, which confers them various types of resistance possibly leading to the MDR phenotype. However, they are classified as multidrug transporters because they expel compounds of contrasting sizes, structures, or electric charges [265]. Thus, RND transporters may be involved in a larger scope of cell functions, and their contribution to the versatility of *S. maltophilia* and their roles in various environments still have to be elucidated. Examples of RND functions ranging from bacterial interactions with plant or animal hosts to the detoxification of metabolic intermediates or the maintenance of cellular homeostasis have been highlighted [266].
<table><caption>**Table 1**

Substrates of Sme RND efflux pumps identified in *S. maltophilia* [268,269,271–299].</caption><thead><tr><th>RND pump</th><th>Antibiotic substrates</th><th>Other substrates</th><th>Reference</th></tr></thead><tbody><tr><td rowspan="3">SmeABC</td><td>Quinolones (ciprofloxacin, levofloxacin)</td><td></td><td>[269]<sup>a</sup>, [271]<sup>b</sup>, [272]<sup>b</sup></td></tr><tr><td>β-lactams*</td><td></td><td>[269]<sup>a</sup></td></tr><tr><td>Aminoglycosides (gentamicin)</td><td></td><td>[272]<sup>b</sup>, [269]<sup>a</sup></td></tr><tr><td rowspan="10">SmeDEF</td><td>Quinolones (ciprofloxacin, levofloxacin, norfloxacin, ofloxacin, nalidixic acid)</td><td></td><td>[268]<sup>d</sup>, [273]<sup>b, e</sup>, [274]<sup>a, b</sup>, [275]<sup>c, e</sup>, [276]<sup>a</sup>, [277]<sup>b, c</sup>, [278]<sup>a, b, c</sup>, [279]<sup>a</sup>, [280]<sup>b</sup>, [281]<sup>a, b</sup></td></tr><tr><td>β-lactams (meropenem, ceftazidime)</td><td></td><td>[271]<sup>b</sup>; [272]<sup>b</sup></td></tr><tr><td>Sulfonamides (trimoxazole: trimethoprim sulfamethoxazole)</td><td></td><td>[282]<sup>a</sup>, [283]<sup>a, e</sup></td></tr><tr><td>Macrolides (erythromycin)</td><td></td><td>[268]<sup>d</sup>, [273]<sup>b, e</sup>, [276]<sup>b</sup>, [278]<sup>a, b, c</sup>, [279]<sup>a</sup></td></tr><tr><td>Cyclins (tetracyclin, tigecyclin, doxycyclin)</td><td></td><td>[268]<sup>d</sup>, [273]<sup>b, c</sup>, [279]<sup>a</sup>, [280]<sup>b</sup>, [284]<sup>c</sup></td></tr><tr><td>Amphenicols (chloramphenicol)</td><td></td><td>[268]<sup>d</sup>, [273]<sup>b, c</sup>, [277]<sup>b, c</sup>, [278]<sup>a, b, c</sup>, [279]<sup>a</sup></td></tr><tr><td>Aminocoumarins (novobiocin)</td><td></td><td>[273]<sup>b, c</sup>, [279]<sup>a</sup></td></tr><tr><td>SDS, crystal violet, acriflavine, proflavine, ethidium bromide</td><td></td><td>[279]<sup>a</sup></td></tr><tr><td>Plant flavonoid: phloretin</td><td></td><td>[276]<sup>a, b</sup></td></tr><tr><td>Stenobactin (siderophore)</td><td></td><td>[285]<sup>b</sup></td></tr><tr><td rowspan="7">SmeGH</td><td>β-lactams (ceftazidime, aztreonam, cefazolin, cefotaxime, cefoxitin)</td><td></td><td>[286]<sup>a, f</sup></td></tr><tr><td>Quinolones (norfloxacin)</td><td></td><td>[286]<sup>a, f</sup>, [287]<sup>a, b</sup></td></tr><tr><td>Amphenicols (chloramphenicol)</td><td></td><td>[287]<sup>a, b</sup></td></tr><tr><td>Macrolides (erythromycin)</td><td></td><td>[287]<sup>a, b</sup></td></tr><tr><td>Cyclins (tetracyclin)</td><td></td><td>[286]<sup>a, f</sup>, [287]<sup>a, b</sup></td></tr><tr><td>Oxidative stress agents: menadione and tert-butyl hydroperoxide</td><td></td><td>[286]<sup>a, f</sup></td></tr><tr><td>Plant flavonoid: naringenin</td><td></td><td>[286]<sup>a, f</sup></td></tr><tr><td rowspan="4">SmeIJK</td><td></td><td>Benzalkonium chloride</td><td>[286]<sup>a, f</sup></td></tr><tr><td>Cyclins (tetracyclin, minocyclin)</td><td></td><td>[288]<sup>a, b</sup></td></tr><tr><td>Quinolones (ciprofloxacin, levofloxacin)</td><td></td><td>[288]<sup>a, b</sup></td></tr><tr><td>Aminoglycosides</td><td></td><td>[289]<sup>a</sup></td></tr><tr><td></td><td>Macrolides (leucomycin)</td><td></td><td>[289]<sup>a</sup></td></tr></tbody></table>
<table><tbody><tr><td>SmeMN</td><td></td><td></td><td></td></tr><tr><td>SmeOP-TolCsm</td><td>Cyclins (doxycyclin)<br>Quinolones (nalidixic acid)<br>Aminoglycosides (amikacin, gentamicin, kanamycin*, tobramycin*)<br>Macrolides (erythromycin, leucomycin, rokitamycin*, spiramycin*)<br>Sulfonamides* (co-trimoxazole: trimethoprim sulfamethoazole)<br>Amphenicols* (chloramphenicol)<br>β-lactams* (piperacillin, carbenicillin, cefoxitin, cefuroxime, aztreonam)</td><td>[290]<sup>a</sup>, [291]<sup>a</sup><br>[290]<sup>a</sup>, [291]<sup>a</sup><br>[290]<sup>a</sup>, [291]<sup>a</sup><br>[290]<sup>a</sup>, [291]<sup>a</sup><br>[290]<sup>a</sup><br>[290]<sup>a</sup><br>[290]<sup>a</sup></td><td></td></tr><tr><td></td><td>Carbonyl cyanide 3-chlorophenylhydrazone (CCCP), crystal violet, sodium dodecyl sulfate (SDS), tetrachlorosalicylanilide (TCS), acriflavine*, fusaric acid*, menadione*, paraquat*, plumbagin*</td><td>[290]<sup>a</sup>, [291]<sup>a</sup></td><td></td></tr><tr><td>SmeUIVWU2X</td><td>Sulfonamides (co-trimoxazole: trimethoprim sulfamethoazole)<br>Quinolones (ofloxacin, ciprofloxacin, levofloxacin)<br>Aminoglycosides (amikacin, gentamicin)<br>Cyclins (tetracyclin)<br>Amphenicols (chloramphenicol)<br>Probably vitamin K3 (menadione)<br>Superoxide-mediated oxidized products</td><td>[283]<sup>b</sup>, [292]<sup>b</sup><br>[274]<sup>a, b</sup>, [276]<sup>b</sup>, [281]<sup>a, b</sup>, [293]<sup>a</sup>, [294]<sup>a</sup>, [295]<sup>b</sup><br>[294]<sup>a</sup><br>[294]<sup>a</sup><br>[294]<sup>a</sup><br>[296]<sup>a</sup><br>[292]<sup>b</sup></td><td></td></tr></tbody></table>
<table><tr><td rowspan="5">SmeYZ</td><td>Aminoglycosides (amikacin, gentamicin, kanamycin, streptomycin)</td><td>[275]<sup>a</sup>,<sup>c</sup>, [278]<sup>b</sup>,<sup>c</sup>, [288]<sup>a</sup>, [293]<sup>a</sup>, [297]<sup>c</sup>, [298]<sup>a</sup>, [299]<sup>a</sup></td></tr><tr><td>Sulfonamides (trimoxazole: trimethoprime sulfamethoazole)</td><td>[298]<sup>a</sup></td></tr><tr><td>Polypeptides (polymixin B)</td><td>[299]<sup>a</sup></td></tr><tr><td>Stenobactin (siderophore)</td><td>[285]<sup>b</sup></td></tr></table>

Methods of substrate identification: <sup>a</sup> deletion mutant / use of an inhibitor; <sup>b</sup> qRT-PCR or transcriptional fusion; <sup>c</sup> regulator mutant; <sup>d</sup> heterologous expression; <sup>e</sup> Western blot/proteomics; <sup>f</sup> mutation of the RND pump. * substrate only associated with the OMP function. Antibiotic families: quinolones (blue), β-lactams (green), aminoglycosides (orange), sulfonamides (red), macrolides (pink), cyclins (purple), amphenicol (yellow), polypeptides (lime), aminocoumarin (light blue).

The RND superfamily is subclassified depending on the phylogenetic distance and the nature of the substrates. Four families are encountered among Gram-negative bacteria [263], namely the Hydrophobe Amphiphile Efflux (HAE) family which transports hydrophobic and amphiphilic substrates, the HAE-1 family that exports a large variety of molecules such as drugs or organic molecules, the Heavy Metal Efflux (HME) family which handles heavy metals, and the Nodulation Factor Exporter (NFE) family [263,267]. Eight RND efflux pumps have been characterized in *S. maltophilia*, namely SmeABC, SmeDEF, SmeGH, SmeIJK, SmeMN, SmeOP-TolC<sub>sm</sub>, SmeU<sub>1</sub>VWU<sub>2</sub>X, and SmeYZ [12,268,269]. They all belong to the HAE-1 family. They are distributed throughout the species, except a few isolates that do not harbor one of them [14]. Other RND efflux complexes have been identified in some strains, but none has been described to our knowledge, except EbyCAB in strain BurA1 [14,270]. The role of these RND pumps is mainly described in antibiotic resistance and in the emergence of the MDR phenotype. However, RND systems have multiple roles beyond the uptake of antibiotics and clinically relevant molecules, for which they are most studied. In fact, these molecules can be an unintended substrate within the broad spectrum of RND efflux systems [18]. The primary ecological role of RND pumps has been underexplored regarding the extreme versatility of the species, and an insight into the other functions of RND pumps is needed. A more comprehensive identification of the substrates of each pump could help to better understand their function(s) and their main role in the cell. Below are described the functions of each RND efflux pump, based in particular on the substrates already described and summarized in Table 1. It should be noted that the functions and substrates of certain pumps remain poorly described or even unknown, e.g. for SmeMN.

### 3.1. Role in resistance to antibiotics and toxicants

RND efflux pumps confer *S. maltophilia* resistance to ten different classes of antibiotic molecules and to many other biocides identified as substrates of one or more of them (Table 1). They play a central role in antibiotic resistance at both intrinsic and acquired resistance levels. Intrinsic resistance of *S. maltophilia* is mainly provided by the SmeDEF, SmeGH, SmeIJK, and SmeYZ pumps [12,273, 279,286,288,298], while SmeABC, SmeDEF, and SmeU<sub>1</sub>VWU<sub>2</sub>X are directly linked to the emergence of the MDR phenotype [268,269, 273,294,300].

Other substrates of Sme pumps than antibiotics have been identified (Table 1). The uptake of toxic exogenous compounds by RND pumps contributes to the ability of *S. maltophilia* to colonize and adapt to a broad range of niches because these efflux systems confer resistance to various toxicants found in the environment. In particular, SmeDEF, SmeGH, and SmeOP-TolC<sub>sm</sub> can detoxify the cell from diverse toxic molecules including detergents, disinfectants, intercalants, inhibitor of oxidative phosphorylation, antiseptics, and dyes. Enhanced tolerance to hexane has been noted when the SmeMN pump is overexpressed [279]. These data highlight the importance of RND pumps in overall cell detoxification thanks to the wide range of molecules they can transport.

### 3.2. Role in cell physiology and the stress response

RND pumps are involved in many other cellular functions than detoxification [266]. Many RND pumps – SmeABC, SmeDEF, SmeIJK, and SmeYZ – have been associated with *S. maltophilia* physiological functions. When SmeDEF is overexpressed, fitness is impaired, colony growth is reduced, and the growth rate is altered [301]. These results indicate that SmeDEF is key for the cell physiology, and its activity is related to the maintaining of membrane integrity [301]. SmeYZ may be implied in the extrusion of substrates part of the extracellular matrix: the knock-out mutant ΔsmeYZ displayed impaired growth, a reduced colony size, and higher hydrophobicity, without the morphology of each cell being affected [298]. Furthermore, while substrates have been associated with SmeC, none have been identified for SmeAB (see section 4.2). Nevertheless, the SmeABC pump is involved in cell physiology functions:
hyper-expression of smeABC negatively affects the growth rate, and deletion of smeC reduces cell size and decreases Gram cell staining [269]. Finally, SmeIJK is related to cell membrane integrity: loss of smeIJK compromises the cell envelope integrity and activates the σE regulon involved in the stress response [289].

RND pumps also contribute to various stress responses. Implication in the oxidative stress response is documented for SmeU1V-WU2X, SmeGH and SmeYZ [286,292,298,302]. Superoxide-mediated oxidized products and probably menadione have been identified as substrates of SmeU1VWU2X [292,296]. Deletion of SmeYZ leads to higher susceptibility to menadione and hydrogen peroxide (H₂O₂) [298], while SmeGH confers resistance to menadione and *tert*-butyl hydroperoxide – two superoxide-generating compounds [286]. More recently, SmeYZ, and to some extent SmeDEF when smeYZ is depleted, have been showed to participate to iron ho-meostasis by exporting stenobactin, the sole siderophore in *S. maltophilia* [285].

### 3.3. Role in virulence

RND efflux pumps play a role in other cellular functions. SmeYZ is notably involved in virulence traits of the species. Lin *et al.* (2015) [298] characterized the virulence traits affected in a ΔsmeYZ mutant. They observed missing flagellae and motility, and reduced biofilm formation later confirmed by Kim *et al.* (2018) [303]. SmeGH is also involved in biofilm formation: a ΔsmeH mutant showed a higher capacity to produce a biofilm [286]. Protease secretion is another function associated to RND efflux systems. Both SmeDEF and SmeYZ are associated with protease secretion activity [298,303,304] and share overlapping physiological functions when it comes to protease secretion [304].

SmeDEF, SmeGH and SmeYZ are implied in *S. maltophilia* virulence against eukaryotes. A strain overexpressing SmeDEF displayed decreased virulence against the social amoeba *Dictyostelium discoideum* [301]. Likewise, deletion of EbyCAB – an RND efflux pump specific to *S. maltophilia* BurA1 strain – displayed increased virulence against *D. discoideum* [270]. Conversely, deletion of SmeYZ induced decreased virulence against mice and higher susceptibility to human serum and neutrophile-mediated killing [298]. These observations suggest that these RND pumps are involved in virulence.

### 3.4. Role in the interactions with other organisms

*S. maltophilia* interacts with many organisms (see section 2.2). Its wide association with plants can be related with substrates of Sme RND efflux pumps of plant origin and provides leads to their involvement in these interactions. Phloretin and naringenin (two plant-produced flavonoids) have been identified as substrates of SmeDEF and SmeGH, respectively (Table 1). As SmeDEF is involved in resistance to plant-produced flavonoids, an original function for this pump in plant root colonization has been proposed, confirming the probable role of RND pumps in interactions with eukaryotic organisms [276]. RND pumps are also implied in interactions with free-living amoebas: *smeDEF* and *smeYZ* were overexpressed in contact with the supernatant of an amoeba/*S. maltophilia* co-culture [305], while the BurA1 strain depleted for EbyCAB multiplied more in different free-living amoeba genera [270].

## 4. Genetic and structural organization of *S. maltophilia* RND efflux pumps

### 4.1. Organization of RND efflux pumps

Beyond substrates, the ecological role of RND pumps can be clarified by understanding their genetic organization and the related regulatory mechanisms in relation to the inducer molecules. *S. maltophilia* genetic organization differs depending on RND efflux pumps (Fig. 1-A, 1-B). Conventionally speaking, genes encoding the pumps are organized in operons, and each component of the pump is encoded in one operon [267], e.g. MexAB-OprM in *Pseudomonas aeruginosa* [306] or the OMP encoded elsewhere like AcrAB-TolC in *Escherichia coli* [307]. These two types of organization are found in *S. maltophilia*, but some pumps present yet another genetic arrangement.

The operons coding for SmeABC, SmeDEF, and SmeU1VWU2X are the only three operons displaying genes coding for MFP, IMP, and OMP (in this order). The operon smeU1VWU2X presents the same organization as the smeV, smeW, and smeX genes encoding MFP, IMP, and OMP, respectively. However, smeU1 and smeU2 surrounding the genes of the RND pumps code for two short-chain de-hydrogenases/reductases (SDR) [294]. The function of SmeU1VWU2X is enhanced by the action of SmeU2, that can detoxify superoxide-mediated toxicants subsequently extruded by the pump [292,294]. SmeU1VWU2X is a quiescent pump not constitutively expressed or expressed at a low level, but its expression can be induced [276,294]. Its overexpression can result from mutations in its regulator SmeRv conferring resistance to bacteria [295].

*smeOP-tolC*<sub>sm</sub> also has an original genetic organization with an OMP-coding gene – *tolC*<sub>sm</sub> – inversely oriented compared to *smeO* and *smeP* coding for MFP and IMP, respectively. Although *smeO* and *smeP* are not encoded in the operon with *tolC*<sub>sm</sub>, they share the same intergenic region [291]. *tolC*<sub>sm</sub> is organized in an operon with the *smeR*<sub>o</sub> and *pcm* genes coding for a TetR-type transcription regulator [291] and a protein-L-isoaspartate O-methyltransferase (PCM) [290], respectively. PCM – an enzyme that can recognize and catalyze the repair of damaged L-isoaspartate O-methyltransferase groups in proteins – is probably involved in the repair of damage caused to TolC<sub>sm</sub> and in keeping the OMP functional [291]. *pcm-tolC*<sub>sm</sub> is not subjected to the regulatory control of SmeR<sub>o</sub> and is constitutively expressed [291].

The three components are not part of the same transcription unit in the other RND pumps. No OMP gene has been found near the smeGH, smeIJK, smeMN, and smeYZ operons. They probably use an OMP encoded elsewhere in the genome. It is well documented in *E. coli* that its OMP TolC can be shared among RND efflux pumps but also with other efflux pump families [308,309]. RND proteins can
interact with the Outer Membrane Factors (OMF) family, MFS or ABC transporter superfamilies [264]. This demonstrates the complexity of the interactions among all efflux systems and enhances their efficacy [265,310].

SmeIJK is the only operon encoding one MFP with two IMPs and no OMP. We could hypothesize that two different RND efflux pumps are encoded in this operon, probably with different substrate specificities for each IMP. This pump is constitutively expressed, probably due to its role in preventing envelope stress [12,289]. SmeIJK could also be associated with the OMP TolC<sub>sm</sub> [290].

The last three RND pump operons – *smeGH*, *smeMN*, and *smeYZ* – are composed of two genes coding for an MFP and an IMP, respectively [12]. This type of organization has already been described for some of the Mex pumps in *P. aeruginosa* [306] and for some Mdt and Acr pumps in *E. coli* [307], and no OMP is associated genetically. Only SmeYZ and SmeGH are probably associated with the OMP TolC<sub>sm</sub> [287,290] and is constitutively expressed at a significant level [288,298].

## 4.2. Redundancy and association

Functional redundancy, characterized by overlapping functions of several efflux systems, can confer better adaptation and a better survival strategy to bacteria [265]. Many molecules can be extruded by more than one *S. maltophilia* efflux pump (Table 1). A good example of this phenomenon is resistance to quinolones conferred by SmeDEF, SmeU<sub>1</sub>VWU<sub>2</sub>X, and SmeGH. While SmeDEF and SmeU<sub>1</sub>VWU<sub>2</sub>X are the main pumps involved in quinolone resistance, SmeU<sub>1</sub>VWU<sub>2</sub>X is involved in this resistance when SmeDEF is not overexpressed [276,285]. However, when both SmeDEF and SmeU<sub>1</sub>VWU<sub>2</sub>X are deleted, SmeGH offsets their loss and contributes to acquired fluoroquinolone resistance in strains where it is overexpressed [287].

As the lack of one of the three components of an RND pump impairs its function, various associations exist between different efflux systems [265]. The absence of an OMP in some RND operons or the sharing of the OMP TolC<sub>sm</sub> between SmeIJK, SmeGH, SmeYZ, and SmeOP reinforces the assumption of some kind of coordination between RND systems and probably other efflux pumps. Furthermore, not only does the porin SmeC interact with SmeA and SmeB, but it is also involved along with other efflux systems and possesses its own weak promoter [269]. Only SmeC is implied in resistance to β-lactams and the MDR phenotype independently of SmeA and SmeB, probably in association with another undetermined transporter [269], even if a more recent study showed a correlation between the MDR phenotype in clinical isolates and *smeA* overexpression [300]. Similarly, as SmeF can operate with other – although unknown – efflux systems [279], we could hypothesize that *smeF* has its own regulation pathway, as observed for *smeC*. *smeF* expression is notably more stable than that of *smeD* and *smeE* [268].

Besides functional redundancy, coordinate expression of SmeDEF and SmeYZ surprisingly does not induce resistance to their respective substrates but can confer extended drug resistance [304]. The same observation was done with simultaneous SmeU<sub>1</sub>VWU<sub>2</sub>X and SmeDEF overexpression, which did not increase each resistance level but extended the resistance spectrum, allowing the support of a wider variety of substrates [281]. Another example is the coordinate overexpression of SmeIJK and SmeYZ, responsible for an extended drug-resistant profile in clinical mutant isolates [288]. Therefore, overexpression of an RND pump generally increases the spectrum of antibiotics they can extrude. In consequence, *S. maltophilia* can acquire resistance to a new class of antibiotics and thus contribute to the emergence of the MDR phenotype.

Co-regulation can occur between different antibiotic resistance mechanisms, e.g. for the so-called *smeABC* operon and L2 β-lactamase genes. In this context, *smeC* deletion reduces β-lactamase activity [269]. Thus, the mechanisms linking the different RND pumps to each other and to other resistance systems remain unsolved and need to be studied in more detail.

# 5. Regulation and inducers of RND efflux pumps

Understanding the fine regulation mechanisms including i<sup>o</sup>) the regulators and regulator ligands involved in pump expression induction and ii<sup>o</sup>) the conditions under which pump expression is induced or repressed would be another way of trying to elucidate the ecological role of efflux systems. RND pumps are regulated by a variety of complex pathways combining both global and specific transcriptional regulation mechanisms [311,312]. Translational regulation is rare for RND pumps; transcriptional regulation is mainly described [311]. Global regulation allows the bacterium to respond to its environment and coordinate the transcription of genes in different metabolic pathways, whereas specific regulation includes activators and repressors controlling a single operon [313,314]. One-component and two-component systems are the two different types of transcriptional regulators encountered. The most abundant one in prokaryotes is the one-component system, where a sole protein combines sensory and output functions [315]. Conversely, two-component systems are composed of two proteins each assuming the sensory or the output function [316]. Overall, pumps are mainly regulated by repressors, even though activators may exist, particularly when regulation is associated with a global regulation pathway [311]. The specific and global regulatory pathways identified for each pump are described hereafter, and set against known inducer molecules (listed in Table 2). Fig. 2 combines all identified specific and global regulatory mechanisms, the inducer molecules involved and the known substrates for each *S. maltophilia* RND efflux pump. The identification methods of the regulatory mechanisms are available in Supp data 1.

## 5.1. Specific regulation of RND efflux pumps

*S. maltophilia* RND pumps are specifically regulated by TetR or LysR family transcriptional regulators mostly encoded in a cluster located near the efflux pump operon (Fig. 1-B; Fig. 2).
<table><caption>**Table 2**
Inducers of Sme RND efflux pump gene expression identified in *S. maltophilia* [276,292,293,296,297,302,305,317–319].</caption><thead><tr><th>RND efflux pump</th><th>Inducing molecules</th><th>Reference</th></tr></thead><tbody><tr><td>SmeABC</td><td>unknown</td><td>-</td></tr><tr><td rowspan="3">SmeDEF</td><td>Plant flavonoids: apigenin, coumestrol, genistein, naringenin, phloretin, quercetin</td><td>[276]<sup>a</sup></td></tr><tr><td>Unknown metabolite produced during interactions with free-living amoeba</td><td>[305]<sup>a</sup></td></tr><tr><td>Hexachlorophene, triclosan and benzalkonium chloride</td><td>[317]<sup>a</sup>, [318]<sup>a</sup>, [319]<sup>a</sup></td></tr><tr><td>SmeGH</td><td>Plant flavonoid: phloretin*</td><td>[276]<sup>a</sup></td></tr><tr><td>SmeIJK</td><td>unknown</td><td>-</td></tr><tr><td>SmeMN</td><td>unknown</td><td>-</td></tr><tr><td rowspan="2">SmeOP-TolCsm</td><td>Plant flavonoid: phloretin</td><td>[276]<sup>a</sup></td></tr><tr><td>Menadione (vitamin K3)</td><td>[296]<sup>b</sup></td></tr><tr><td rowspan="4">SmeU<sub>1</sub>VWU<sub>2</sub>X</td><td>Compounds related to thiol reactivity: iodoacetate, clioquinol, sodium selenite</td><td>[293]<sup>b</sup></td></tr><tr><td>Menadione, plumbagin, hydrogen peroxide</td><td>[292]<sup>a, b</sup></td></tr><tr><td>Reactive oxygen species (ROS)</td><td>[302]<sup>a</sup></td></tr><tr><td>Signals linked to ribosome-stalling stress</td><td>[293]<sup>b</sup></td></tr><tr><td rowspan="3">SmeYZ</td><td>Boric acid, erythromycin, chloramphenicol, lincomycin</td><td>[293]<sup>b</sup></td></tr><tr><td>Mutations in RplA, gentamicin, minocyclin</td><td>[297]<sup>c</sup></td></tr><tr><td>Unknown metabolite produced during interactions with free-living amoeba</td><td>[305]<sup>a</sup></td></tr></tbody></table>

Identification methods: a qRT-PCR; b transcriptional fusion; c Western blot/proteomics; *

hypothesized. Antibiotic families: macrolides (pink), amphenicols (yellow), cyclins (purple), aminoglycosides (orange), lincosamides (green).
### 5.1.1. TetR transcriptional repressor family

Several *S. maltophilia* TetR family regulators have been identified for RND pumps (Table 2; Fig. 2). These one-component systems are involved in antibiotic resistance regulation and are usually repressors [320]. The best characterized one is SmeT, whose structure was obtained by crystallography [321]. SmeT is a transcriptional repressor that inhibits the expression of smeDEF by binding the intergenic region smeT-smeDEF where the two promoters overlap [322,323]. The repressing effect of SmeT on smeDEF expression was confirmed in clinical strains where mutations of smeT induced by repeated exposure to tigecycline led to overexpression of the pump [284]. Several identified inducers (ligands) of smeDEF expression such as triclosan, benzalkonium chloride, and plant flavonoids (apigenin, genistein, naringenin, phloretin, and quercetin) bind directly to SmeT, and induce the dissociation of the SmeT-smeDEF complex and the expression of smeDEF [276,317,319,321]. Other inducer molecules have been identified for SmeDEF expression (Table 2), and studies could be conducted to determine if they are also SmeT ligands.

SmeT is negatively regulated by a putative glycosyl transferase Smlt0622 that can act on a ligand of SmeT [275]. As this enzyme is implied in multiple cellular functions, association of SmeT with more global physiological pathways is suggested. Inactivation of smlt0622 surprisingly induced overexpression of both SmeDEF and SmeYZ, while these pumps are supposed to be inversely regulated by SmeSyRy [275]. This illustrates the great complexity of these regulatory mechanisms, with possible cross-regulation or co-regulation between RND efflux complexes.

Other TetR family repressors have been annotated but remain less characterized than SmeT. For instance, SmeR₀ is organized in an operon with *pcm-tolC*<sub>sm</sub> near the *smeOP* operon, and probably represses the expression of *smeOP* [291]. Another putative TetR transcriptional regulator has also been annotated nearby the EbyCAB pump specific to strain BurA1, but remains uncharacterized too [14].

<figure><img src="image_3.png" /><figcaption>**Fig. 1.** Schematic organization of the different *S. maltophilia* RND efflux pump genes organized in operons and associated regulatory genes. (A) RND efflux pumps are tripartite systems comprising an Inner Membrane Protein (IMP; blue) and an Outer Membrane Protein (OMP; green) inserted in the inner and outer membranes, respectively, and linked by a Membrane Fusion Protein (MFP; yellow) in the periplasmic space. (B) The gene orientation is indicated by the arrow. Arrow colors: genes coding for the OMP (green), the MFP (yellow), the IMP (blue), a short-chain dehydrogenase/reductase (brown), a TetR family regulator (purple), a LysR family regulator (red), a two-component system (pink) and an L-isoaspartate O-methyltransferase protein (gray). (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)</figcaption></figure>
<figure><img src="image_4.png" /><figcaption>**Fig. 2.** Encoding genes, protein organization, regulation, inducers, and substrates of *S. maltophilia* RND efflux pumps. RND efflux pumps are inserted in the bi-layer membrane and their genes are encoded in operons. Global regulatory mechanisms, specific regulators and inducer molecules interact to modulate the expression of RND efflux pump genes. Proteins and their respective encoding genes are represented in yellow for MFPs, in blue for IMPs, and in green for OMPs. The gene orientation is indicated by the arrow. Each line symbolizes a different type of connection between genes, regulatory mechanisms, proteins, substrates and inducer molecules. OMPs can be shared between the different RND systems, and the green bold dotted lines represent the association between IMP/MFP and an OMP encoded elsewhere in the genome. The bold black solid line symbolizes the efflux of molecules through the pump. Dark blue molecules, known antibiotic substrates of RND efflux pumps; light blue molecules, non-antibiotic substrates. The links between the operon and the regulatory systems, physiological responses and stresses are represented by thin black lines with an arrowhead for a positive effect (induction) and lines ending in a small perpendicular line for a negative effect (repression). Dotted lines, mode of action unknown; solid lines, mode of action described. The inducers of RND gene expression (purple compounds) are linked to the induced genes by purple dotted lines when the involved regulators are unknown, or by purple solid lines when they are known. The inducers are also linked to global regulatory pathways by pink solid lines when a direct effect is described or by dotted lines when it is hypothesized. Question marks indicate unknown substrates or protein identity. See Tables 1 and 2 for details on the substrates and inducer molecules. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)</figcaption></figure>
### 5.1.2. LysR transcriptional activator family

Another type of transcriptional regulator of RND system expression is the LysR family involved in the regulation of cellular processes and acting as an activator or a repressor of expression [324]. For instance, SmeR<sub>v</sub> is involved in the positive regulation of *smeU*<sub>1</sub>*VWU*<sub>2</sub>X (Table 2; Fig. 2), but it may serve as a positive and negative modulator in the presence of an activator ligand, like other regulators of this family do [294]. Overexpression of *smeU*<sub>1</sub>*VWU*<sub>2</sub>X following mutation in SmeR<sub>v</sub> confers resistance to quinolones in strains where SmeDEF is not overexpressed [276]. In accordance with the involvement of SmeU<sub>1</sub>*VWU*<sub>2</sub>X in the oxidative stress response, SmeR<sub>v</sub> is positively regulated by SoxR as it is a member of the SoxR regulon responsible for the *S. maltophilia* oxidative stress response mediated by menadione – a superoxide-generating compound - [292]. This is consistent with the inducer molecules identified for this pump (Table 2) and related to the generation of oxidative stress. Molecules associated with oxidative stress generation such as menadione and plumbagin – two superoxide-generating compounds –, reactive oxygen species (ROS) like hydrogen peroxide, or superoxide-mediated oxidized products have indeed been identified as inducers of *smeU*<sub>1</sub>*VWU*<sub>2</sub>X expression [292,296,302]. Thus, these inducers may act on *smeU*<sub>1</sub>*VWU*<sub>2</sub>X expression by activating the SoxR and SmeR<sub>v</sub> pathways. Other toxic molecules like cloquinol, iodoacetate, and sodium selenite have been identified as inducers of *smeU*<sub>1</sub>*VWU*<sub>2</sub>X expression [293]. They can induce modifications in thiol group-containing proteins, and generate global stress [325].

AzoR is encoded elsewhere in the genome. It is constitutively and abundantly expressed, and is responsible for the low basal level of expression of the *smeU*<sub>1</sub>*VWU*<sub>2</sub>X operon through repression of its expression [326]. Like SmeR<sub>v</sub>, AzoR is positively regulated by the SoxR regulon, supporting the role of SmeU<sub>1</sub>*VWU*<sub>2</sub>X in the response to oxidative stress [326]. SmeR<sub>v</sub> and AzoR are two more examples of a specific regulator controlled by the global regulatory pathways of the cell.

## 5.2. Two-component regulatory systems at the junction of global and specific regulation

Two-component regulatory systems (TCSs) consist of a sensor kinase and a response regulator, and allow the bacterium to adapt to modifications in its environment or of its intracellular status [316]. TCSs participate both to specific and global regulation, but are usually an uncommon mode of regulation of RND pumps [327]. Nonetheless, many TCS systems have been associated with the regulation of *S. maltophilia* RND pumps.

An example of TCS acting on the expression of two different RND pumps is SmeSyRy (Table 2; Fig. 2), which acts inversely on the expression of *smeDEF* and *smeYZ* and is composed of SmeSy (a sensor kinase) and SmeRy (a response regulator) [304]. This system represses the expression of *smeDEF* and activates that of *smeYZ*. *smeYZ* is regulated by both SmeSy and SmeRy, but *smeDEF* is only regulated by SmeSy, which most probably interacts with another unidentified response regulator. Furthermore, *smeSyRy* is down-regulated by an unknown mechanism when *smeDEF* is overexpressed [304].

SmeYZ pump expression is controlled by two additional TCSs not encoded in its operon (Table 2, Fig. 2). The first one is PhoPQ, which positively regulates *smeYZ* and is autoregulated and activated by low Mg<sup>2+</sup> concentrations and other stress conditions [299]. The second one is SmaRS, composed of a transcriptional regulator SmaR and a sensor kinase SmaS. SmaS activates overproduction of SmeYZ as SmeSyRy does, and is co-regulated with an ABC-transporter [275], illustrating shared regulatory pathways with other efflux systems. The last TCS identified in the regulation of *S. maltophilia* RND efflux pumps is SmeRS encoded upstream of the *smeABC* operon (Table 2, Fig. 2). It is composed of SmeR and SmeS – a transcriptional activator and a sensor kinase, respectively [269]. SmeR positively regulates the expression of *smeABC* genes in response to a yet unidentified stress and autoregulates its own operon [269].

## 5.3. Global regulation of RND efflux pump genes

Global regulation allows a coordinate response of the bacterium to changes in its environment. Thus, global regulation of RND efflux systems contributes to the versatility of the species through adaptation to its environment. Different levels of regulation can coexist for one efflux pump and even be shared between two pumps. For instance, two levels of regulation have been identified for SmeDEF, and growth-dependent regulation has also been noted [268]. *smeDEF* operon expression depends on the growth phase: maximum expression is reached at the beginning of the exponential phase and then decreases during the stationary phase, until it becomes undetectable after 24 h [268]. This growth-dependent expression can be linked to the physiological functions previously described for SmeDEF.

### 5.3.1. General stresses

As illustrated before, indirect regulation occurs in response to the cell physiology or stresses. Thus, global cell processes can also regulate the expression of RND efflux pumps. Induction of a signaling cascade may or may not act directly on the expression of the pumps following a signal received by the cell. ClpA and HtpX are two proteases responsible for intrinsic resistance to aminoglycosides [328]. When ClpA and HtpX are depleted, SmeYZ pump-mediated aminoglycoside resistance is weakened, suggesting a probable involvement of these proteins in the activity of SmeYZ [328]. Other examples of general regulation exist in response to bacterial stress, including oxidative stress. In particular, a link between *rpoE* – a gene involved in the stress response – and *smeIJK* expression has been established, with possible direct regulation of this RND pump by the RpoE system [289]. In fact, *smeIJK* is part of the *σ*<sup>E</sup> regulon along with *rpoE-resA-mucD*, and is needed to manage envelope stress [289]. This regulation in response to envelope damage is in accordance with identified functions of SmeIJK in cell physiology (see section 3.2).

The expression of RND efflux pumps is also induced by natural and synthetic molecules classified as biocides. For instance, *smeDEF* expression is induced by three synthetic disinfectants – benzalkonium chloride, hexachlorophene, and triclosan [317–319] – and *smeYZ* expression is induced by boric acid – a natural antiseptic [293] –. Even if the modes of action of these molecules remain unclear,
they may have multiple targets in the cell and contribute to generate general stress.

### 5.3.2. Environmental inducers

The molecules identified as inducers of RND pump expression are mostly of environmental origin. Several plant flavonoids can induce smeDEF, smeOP-tolC<sub>sm</sub>, and probably smeGH expression (Table 2). Concerning SmeDEF, no less than six flavonoids have been identified as inducers, supporting the idea that this pump has a primary ecological role in plant colonization [276]. These three pumps could play a part in the colonization of the large range of rhizospheres where *S. maltophilia* can be found (see section 2.2.1). Moreover, smeDEF expression, in addition to SmeYZ expression, is also induced by an unknown secondary metabolite produced upon interaction with the amoeba *Acanthamoeba castellanii* [305], suggesting a function of SmeYZ and SmeDEF during the interactions with eukaryotic organisms. The uptake of compounds from other organisms by RND pumps could contribute to the interaction of *S. maltophilia* in its natural environment and promote the colonization of various ecological niches. Given the number of niches colonized by *S. maltophilia*, many molecules that induce pump expression have yet to be discovered. We can also question the way these inducers of pump expression interact with previously described specific regulators or global regulatory pathways. Few inducer molecules of smeDEF expression have been identified as ligands of its specific regulator SmeT, and the mode of action of the other inducers remains unknown.

### 5.3.3. Antibiotics as inducers?

No link can be made between the substrates and inducers of each RND pump. While antibiotics are the main substrates of the pumps in *S. maltophilia*, very few of them can induce their expression (Table 2). Likewise, many antibiotics are supported by seven *P. aeruginosa* RND pumps, but none of them is involved in the regulation of their expression [18,329]. In *S. maltophilia*, only smeYZ expression can be induced by antibiotics. Yet, no evidence of direct binding of the antibiotic to a regulator of smeYZ has been provided; indirect induction in response to ribosomal stress caused by antibiotic molecules is more likely. Regulation by antibiotics can be indirect and follow from the accumulation of toxic metabolism by-products or metabolism intermediates leading to the induction of efflux systems as a result of the generated stress [18]. The RND system is induced by metabolic pathway intermediates in *E. coli* [330]. In *S. maltophilia*, smeYZ expression is also probably induced by a signal linked to ribosome-stalling stress [293]. Gentamicin, erythromycin, lincomycin, chloramphenicol, and minocycline act directly or indirectly on ribosomal subunits by targeting the protein or inhibiting its biogenesis, and disrupt translation in cells. In the same way, boric acid – a natural toxic antiseptic that inhibits protein synthesis – and mutation of RplA – a ribosomal protein – are also inducers of smeYZ expression [293,297].

The presence of antibiotic-resistant strains in non-clinical environments suggests that these general resistance systems are induced by other molecules than antibiotics themselves. Nonetheless, beyond the few compounds recognized as inducers of RND pump expression, the conditions leading to this induction remain unknown. Most results point to induction in natural environments based on the origin of the molecules. However, many inducers still remain to be elucidated. It is noteworthy that no inducer molecule of the SmeABC, SmeMN and SmeLJK pumps has been identified to date.

These previously described mechanisms of induction are consistent with the global regulatory patterns that govern the expression of some pumps. They reinforce the involvement of RND pumps in the general operating processes of the cell. Based on the regulatory mechanisms and identified inducers, some *S. maltophilia* RND efflux pumps are involved in the general stress response of the bacterium, and probably extrude toxic compounds, metabolic by-products, or other factors essential in the response to various global cellular stresses. These observations highlight that a fine-tuned regulation is needed for efflux pumps to be expressed in the right conditions: a compromise has to be reached between the cell responses to stress/the environment and the fitness cost of efflux pump expression in unsuitable conditions. Constitutive *versus* inducible expression of RND pumps may also reflect their involvement in physiological roles of the cell when the pump is expressed at low levels because overexpression can deregulate the membrane H+ potential of the cell and lead to death [311]. In-depth studies of the regulatory mechanisms, coupled with the identification and characterization of the regulators involved and inducer molecules, would improve our understanding of the primary ecological role of RND efflux pumps. Moreover, even if transcriptional regulation is the main identified regulatory mechanism of RND pumps, the sharing of a same OMP between different pumps – as for TolC<sub>sm</sub> – could suggest regulation resulting in a limiting number of OMPs available in the outer membrane. Finally, the co-existence of several regulatory systems for a same RND pump, as well as examples of regulators modulating the expression of more than one pump, attest the complexity of the regulatory pathways of these pumps. The versatile nature of RND pump regulation is consistent with their role in resistance to a wide variety of substrates as well as other physiological functions that allow them to adapt to diverse environments [312].

## 6. Conclusion and prospects

RND efflux pumps have an ancient evolutionary origin and evolved following duplication of a few primordial systems [263,331] which led to the support of new substrates. Bacterial exposure to clinically relevant drugs over the past decades has not resulted in the emergence of new pumps, which are widely distributed across pathogenic and non-pathogenic bacteria [331]. These observations suggest that RND efflux pumps are good examples of “exaptation” because their function diverged from their initial role in the environment [332,333]. Moreover, their accumulation and conservation in the bacterial core genome reinforce their involvement in bacterial physiology [334] and contribute to the versatile potential of bacteria. The opportunistic pathogen *S. maltophilia* highly exemplifies this fact through its wide occurrence in various niches and the presence of at least 8 RND efflux pumps in its core genome regardless the clinical or environmental origin of the strains [14]. Thus, the RND efflux systems of *S. maltophilia* can contribute to its ability to colonize different environments and survive under a large range of conditions.
Beyond their obvious involvement in the extrusion of antibiotics and clinically relevant molecules, *S. maltophilia* RND pumps can transport other molecules linked to cellular functions like detoxification or the response to various stresses including oxidative, iron or even envelope stresses. They also participate to physiological functions because their regulatory mechanisms are linked to the global physiological response of the bacterium. These roles can partially be elucidated thanks to the regulatory mechanisms and the inducer molecules involved, and represent the conditions under which each pump is expressed or not. The complex regulation of RND pumps includes both specific and global regulatory pathways. It occurs at different levels and is associated with regulatory mechanisms shared between certain RND pumps and more broadly other efflux systems. This cooperation between systems is reinforced by the differential expression of some OMPs and the IMP and MFP encoded in the same operon [268,279,323]. Moreover, very few antibiotics have been identified as inducer molecules although they are the main known substrates of the pumps. The inducers of RND pumps are mostly of natural origin and are sometimes related to functions such as bacterial interactions with eukaryotic organisms or the response to stresses like oxidative stress. Some of them have been associated with regulatory pathways or recognized as the direct ligands of a regulator.

A deeper description of the regulatory mechanisms, inducers, and ligands would provide a more comprehensive picture of the conditions under which these pumps operate and would help to further elucidate the ecological roles of *S. maltophilia* RND pumps. Crystallography and docking studies could participate to this gain of knowledge. Inducer molecules could be discovered by modelling the 3D structures of regulatory proteins, as was done for SmeT, in order to identify ligands and in turn potential inducers [276,317,319, 321]. Solving the 3D structure of the RND pump itself would also provide access to conformational information about the tripartite system and help to understand the type of supported substrate by providing keys to the substrate-binding pocket [335]. Moreover, these studies could provide clues about the development of inhibitors of RND efflux pumps, which is a promising therapeutic strategy in the control of antibiotic resistance [336,337]. A more detailed understanding of the structure could help to better address the differences between all RND pumps and refine the knowledge of the roles of the pumps. The specific role of each pump in cellular functions needs to be further investigated. Main functions have already been found, with SmeU1, VWU2, X preferentially associated with the oxidative stress response, SmeIJK with cell membrane integrity and SmeYZ with iron homeostasis. Nonetheless, the role of several pumps remains unknown.

Knowledge about the 8 different pumps of the core genome is uneven, especially in terms of the number of studies per pump, the identification of their role or the description of their substrates, regulatory pathways and inducers. These differences in depth of knowledge between pumps can be explained by an absence of change in antibiotic resistance phenotype when a pump is depleted, related to functional redundancy or to a specific but not yet identified role of the pumps in adaptation to an ecological niche. Since these pumps are shared by both clinical and environmental strains, further study is essential to elucidate their role in the bacterium and in the risk of emergence of antibiotic resistance.

A phylogenetic study was recently conducted on AdeABC, AdeFGH and AdeIJK RND pumps in the *Acinetobacter* genus which revealed the presence of a stable pump and pumps that are unevenly distributed within the species and have undergone several recombination [338]. Moreover, the authors demonstrated that the presence of AdeC can be related to the success of this human pathogen in colonizing hospital environments. Studying the phylogeny of the *S. maltophilia* RND pumps would undoubtedly provide new insights into how selection pressures favor the fixation of mutations in promoter or coding regions of the pumps or in the associated regulators. This approach can also allow deeper understanding of whether the presence of an efflux pump is the result of old or recent duplication or horizontal gene transfer and how these events have contributed to the specific environmental adaptation of the strain and the emergence of highly adapted clinical strains. The phylogeny of the *S. maltophilia* core genome pumps could then be confronted with the phylogeny of the species in order to highlight possible links with genospecies or the origin of the strains. Horizontal gene transfers are rarely described for RND efflux pumps due to the need to transfer all 3 genes of the operon. Only a few examples of plasmid-encoded RND pumps have been described [339–343] but none in *S. maltophilia*. In *S. maltophilia*, the RND EbyCAB pump, specific to the BurA1 strain, is present on a genomic island located in the chromosome and probably results from an old interspecies transfer [14]. However, this pump has not been found in other strain of *S. maltophilia* and currently no role has been identified for this pump.

The existence of RND efflux pumps specific to one strain, such as EbyCAB, raises questions about the potential role played by these specific pumps in phenotypic variations and in the ability of the bacterium to colonize and adapt to new niches or interact with other organisms. Finally, *S. maltophilia* RND efflux systems, including the 8 core-genome associated pumps and the strain-specific pumps may be key to the adaptation of the species to different environmental niches.

**Author contribution statement**

All authors listed have significantly contributed to the development and the writing of this article.

**Funding statement**

A. Chauviat was funded by a grant from the Ministère de l'Éducation Nationale, de l'Enseignement Supérieur et de la Recherche.

**Data availability statement**

Review with no additional data.
**Declaration of interest's statement**

The authors declare no competing interests.

**Additional information**

No additional information is available for this paper.

**Acknowledgments**

We wish to thank Annie Buchwalter for correcting and improving English language prior to publication.

**Appendix A. Supplementary data**

Supplementary data to this article can be found online at https://doi.org/10.1016/j.heliyon.2023.e14639.

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