Resistance to antibiotics of bacteria in tropical countries
Authors: Didier Raoult
Journal: The Lancet Planetary Health (2019)

The search for the source of resistance of bacteria to antibiotics is, I believe, too naive and too much based on guilt for human-related activity. This perception of the world yields analyses that claim to establish an exclusive link between the use of human-made antibiotics and the resistance of microorganisms to antibiotics. This connection neglects the importance of the source of natural antibiotics, which are present in the environment. Most antibiotics are secreted by microorganisms (ie, bacteria) of the actinomycetes phylum, or fungi.1Angelakis E Merhej V Raoult D Related actions of probiotics and antibiotics on gut microbiota and weight modification.Lancet Infect Dis. 2013; 13: 10889-10899Summary Full Text Full Text PDF Scopus (134) Google Scholar The resistance of microorganisms to these natural antibiotics existed long before their medical use. β-lactamases are found in the genetic sequences of microorganisms from the Middle Ages, and the resistance of Staphylococcus aureus in the 19th century has been shown.2Raoult D Rolain JM The living croquet theory: the Staphylococcus aureus paradigm.Int J Antimicrob Agents. 2019; published April 12. DOI:10.1016/j.ijantimicag.2019.04.005Crossref Scopus (1) Google Scholar Antibiotics are assembled in microorganisms by non-ribosomal protein synthases and polyketide synthases, which are the only known translation devices outside the ribosome. Their existence might have preceded that of ribosomes and could be archaic translation machineries. Because biodiversity is generally much higher in the humid intertropical zone, as compared with temperate and cold countries, it is also likely to be the place where the most diverse microorganisms are found, as evidenced by the richness of the human microbiota in rural intertropical areas compared with urban or temperate areas.3Angelakis E Bachar D Yasir M et al.Comparison of the gut microbiota of obese individuals from different geographic origins.New Microbes New Infect. 2019; 27: 40-47Crossref PubMed Scopus (10) Google Scholar This biodiversity can be accompanied by a biodiversity of molecules with antibiotic activity. Additionally, the molecules secreted by non-ribosomal protein synthases and polyketide synthases have multiple activities—not only antimicrobial, but also antifungal. Against eukaryotes, some molecules are used as anticancer treatments. Some human β-lactamases have anticancer drug inhibitory activity as with mitomycin.4Lee SY Brem J Pettinati I et al.Cephalosporins inhibit human metallo β-lactamase fold DNA repair nucleases SNM1A and SNM1B/apollo.Chem Commun. 2016; 52: 406727-406730Google Scholar The spectrum of β-lactamase activity far exceeds anti-β-lactamine activity, playing a role in the digestion of nucleic acid.4Lee SY Brem J Pettinati I et al.Cephalosporins inhibit human metallo β-lactamase fold DNA repair nucleases SNM1A and SNM1B/apollo.Chem Commun. 2016; 52: 406727-406730Google Scholar Antibiotic resistance is a global concern and the source of resistance is often found in the world's intertropical or hottest regions.5Collignon P Beggs JJ Walsh TR Gandra S Laxminarayan R Anthropological and socioeconomic factors contributing to global antimicrobial resistance: a univariate and multivariable analysis.Lancet Planet Health. 2018; 2: e398-e405Summary Full Text Full Text PDF PubMed Scopus (293) Google Scholar This specificity has not yet been satisfactorily explained, but has been supported by an extensive study by James Hassell and colleagues, which shows that a country's overall antibiotic use is not correlated with the proportion of bacterial resistance;6Hassell JM Ward MJ Muloi D et al.Clinically relevant antimicrobial resistance at the wildlife-livestock-human interface in Nairobi: an epidemiological study.Lancet Planet Health. 2019; 3: e259-e269Summary Full Text Full Text PDF PubMed Scopus (39) Google Scholar rather, the relationship is inverse: the lower the percentage of antibiotic prescription, the higher the proportion of antimicrobial resistance.5Collignon P Beggs JJ Walsh TR Gandra S Laxminarayan R Anthropological and socioeconomic factors contributing to global antimicrobial resistance: a univariate and multivariable analysis.Lancet Planet Health. 2018; 2: e398-e405Summary Full Text Full Text PDF PubMed Scopus (293) Google Scholar We have confirmation of this in France, where antibiotic use is one of the highest in the world, and where the proportion of resistance is one of the lowest in the world.7Le Page S Dubourg G Baron SA Rolain JM Raoult D No global increase in resistance to antibiotics: a snapshot of resistance from 2001 to 2016 in Marseille, France.Eur J Clin Microbiol Infect Dis. 2019; 38: 395-407Crossref PubMed Scopus (8) Google Scholar The same is true in the USA, where difficult-to-treat Gram-negative bacteria represent a small proportion of the bacteria isolated from the blood cultures of hospitalised patients.8Raoult D Rolain JM The paradigm of the Shadoks and antibiotic resistance.Clin Infect Dis. 2019; published online March 6. DOI:10.1093/cid/ciz183Crossref Scopus (4) Google Scholar The reason for these differences remains poorly explained. Poor management of prescription of antibiotics in humans has been proposed,5Collignon P Beggs JJ Walsh TR Gandra S Laxminarayan R Anthropological and socioeconomic factors contributing to global antimicrobial resistance: a univariate and multivariable analysis.Lancet Planet Health. 2018; 2: e398-e405Summary Full Text Full Text PDF PubMed Scopus (293) Google Scholar but this explanation only considers human-made antibiotics, neglecting those produced in the environment. Antibiotics can eventually be used as food by other microorganisms, which in turn develop enzymes to digest them for consumption.9Hibbing ME Fuqua C Parsek MR Peterson SB Bacterial competition: surviving and thriving in the microbial jungle.Nat Rev Microbiol. 2010; 8: 115-125Crossref Scopus (1475) Google Scholar Most families of antibiotics can be used as growth factors for soil microorganisms, and the digestion of penicillin and its use as a sole source of carbon has been shown in Escherichia coli transformed in vitro. This finding shows that antibiotics not only kill microorganisms, but also serve as a nutrient, especially in areas rich in environmental microorganisms. In addition, some arthropods have been shown to be capable of secreting penicillins and cephalosporins, leading to a less simplistic view of antibiotics, selection pressure exclusively from human-made drugs, and resistance.10Pontarotti P Raoult D Why do arthropods secrete β-lactams?.Int J Antimicrob Agents. 2019; 53: 4370Crossref Scopus (3) Google Scholar Thus, β-lactam resistance genes are detected in all vertebrates, including humans, but also in archaea, which are not sensitive to β-lactams.11Keshri V Panda A Levasseur A Rolain JM Pontarotti P Raoult D Phylogenomic analysis of β-lactamase in archaea and bacteria enables the identification of putative new members.Genome Biol Evol. 2018; 10: 41106-41114Crossref Scopus (12) Google Scholar Hassell and colleagues' work6Hassell JM Ward MJ Muloi D et al.Clinically relevant antimicrobial resistance at the wildlife-livestock-human interface in Nairobi: an epidemiological study.Lancet Planet Health. 2019; 3: e259-e269Summary Full Text Full Text PDF PubMed Scopus (39) Google Scholar shows that in Nairobi, a city where antibiotic prescribing is extremely low,5Collignon P Beggs JJ Walsh TR Gandra S Laxminarayan R Anthropological and socioeconomic factors contributing to global antimicrobial resistance: a univariate and multivariable analysis.Lancet Planet Health. 2018; 2: e398-e405Summary Full Text Full Text PDF PubMed Scopus (293) Google Scholar the level of resistance of E coli is particularly high, not only in humans, but also in wildlife. This study must put into perspective a much less anthropocentric approach, integrating the fact that antibiotics are probably more than 3 billion years old, as are antibiotic-resistance enzymes, and that we can only understand, and therefore combat antibiotic resistance, if we have a more scientific vision of this world. In conclusion, public health considerations can lead to substantial simplification of a complex issue, in particular to enable the dissemination of simple, understandable health-care messages; however, this process can lead to messaging that is partly false. This issue needs to be acknowledged by the scientific community. Control measures should not prevent the integration of recent scientific data for fear of misuse of antibiotics. This line of thought might end up being dangerous for humans, and more emphasis should be put on the complexity of the relationships between antibiotics and the enzymes that, among others, digest them. I declare no competing interests. Clinically relevant antimicrobial resistance at the wildlife–livestock–human interface in Nairobi: an epidemiological studyUrban wildlife carry a high burden of clinically relevant antimicrobial-resistant E coli in Nairobi, exhibiting resistance to drugs considered crucial for human medicine by WHO. Identifiable traits of the wildlife contribute to this exposure; however, compared with humans, livestock, and the environment, low phenotypic diversity in wildlife is consistent with the hypothesis that wildlife are a net sink rather than source of clinically relevant resistance. Wildlife that interact closely with humans, livestock, and both human and livestock waste within households, are exposed to more antimicrobial resistant phenotypes, and could therefore act as conduits for the dissemination of clinically relevant antimicrobial resistance to the wider environment. Full-Text PDF Open Access