# Metal-Complexes Biomimetic of Metallo-β-Lactamases

Morane Beaumet, Sarah Wiorek, Jean-Pierre Mahy, Wadih Ghattas

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Morane Beaumet, Sarah Wiorek, Jean-Pierre Mahy, Wadih Ghattas. Metal-Complexes Biomimetic of Metallo-β-Lactamases. European Journal of Inorganic Chemistry, 2025, 28 (29), 10.1002/ejic.202500194. hal-05397390

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# Metal-Complexes Biomimetic of Metallo-β-Lactamases

Morane Beaumet, Sarah Wiorek, Jean-Pierre Mahy, and Wadih Ghattas*

Metallo-β-lactamases (MβLs) are bacterial Zn²⁺ dependent enzymes that catalyze the hydrolysis inactivating β-lactam antibiotics. Understanding their mechanism is crucial for developing more potent antibiotics and for designing inhibitors of MβLs paving the way for more effective treatments. To this end, numerous Zn²⁺ complexes that mimic MβLs have been synthesized and studied, leading to the conclusion that often a hydroxyl group coordinated to Zn²⁺ is responsible for the hydrolysis of substrates. In

parallel, research on MβLs has highlighted the importance of the coordination of the substrate to Zn²⁺ and the involvement of the reactive hydroxyl group or of a water molecule in hydrogen bonding to facilitate the hydrolysis. The development of more suitable biomimetic complexes of MβL, which replicate these enzymatic features, can become crucial for obtaining deeper and more accurate mechanistic insights.

## 1. Introduction to Metallo-β-Lactamases

β-lactamases (βLs, Enzyme Commission number 3.5.2.6)[1] are hydrolases that specifically act on the C-N bond of lactams (Scheme 1). They have been classified into four classes: A, B, C, and D.[2] Among them, serine-β-lactamases are thought to follow the classical mechanism of serine hydrolases and are classified by sequence homology into Classes A, C, and D.[3] Their activity is limited to the catalysis of the hydrolysis of constrained-ring β lactams, such as penicillins (Figure 1). The fourth class, "Class B" includes metallo-β-lactamases (MβLs), which coordinate either one or two Zn²⁺. Enzymes in Class B2 coordinate a single Zn²⁺, while those in Classes B1 and B3 coordinate two. These enzymes are thought to follow two similar mechanisms centered on the metal cation. MβLs can catalyze the hydrolysis of unconstrained-ring β lactams such as cephalosporins (Figure 1). Moreover, certain dinuclear MβLs are active on a very broad spectrum of β lactams, including most substrates of the various serine-β-lactamases. These enzymes are of particular interest because their extensive activity poses major health risks.[4]

Given their importance, MβLs are the subject of many studies aimed at understanding their mechanism and at the development of novel, more potent antibiotics as well as MβL-inhibitors.[5] Biomimetic metal-complexes are a minimalistic approach to enzymes consisting in mimicking the structure and/or function of their active sites. The study of such molecular model complexes provides structural and mechanistic insights into the natural enzymes that they mimic. While diverse complexes have been reported to

catalyze β-lactam hydrolysis,[6-9] most of these have already been reviewed,[10] notably by Daumann et al.[11] in a comprehensive analysis that also compared them with natural systems. Our article focuses on those that are Zn²⁺-based and therefore are biomimetic of MβLs, and only the gathered key mechanistic insights are highlighted here through a selection of examples. The limitations of these complexes compared with natural systems are also discussed here. Building on these findings, we propose several promising directions for the design of future models, which would be particularly important for studying metallo-β-lactamases and may also serve as valuable tools for investigating other enzymes.

## 2. Biomimetic Complexes of Mononuclear Metallo-β-Lactamases

In the early 1980s, the hydrolysis of β lactams in alkaline media as well as in the presence of metal cations was described,[12-15] but it was not until 1990 that Przystas and Fife proposed the first complex that mimics MβLs.[16] They synthesized ligands containing amides, including one comprising a β lactam bound to a quinoline. Characterizations that were performed in water and in the presence of Ni²⁺ indicated both the formation of β lactamide complex 1c (c, standing for complex; Figure 2), and the subsequent hydrolysis of its Ni²⁺-bound β lactamide fragment.

### 2.1. Tetraazacyclododecane Complexes

In 1991, Kimura's team synthesized Zn²⁺ complexes based on the 1,4,7,10-tetraazacyclododecane ligand to conduct studies aimed at elucidating the mechanisms of various Zn²⁺ dependent enzymes. For example, complex 2c (Figure 2) was used to investigate the mechanism of phosphatases[17] and MβLs.[18] While the ligand in 2c is tetradentate, the active site of class B2 MβLs is characterized by a tridentate coordination, vide infra. Despite this important structural difference, the complex exhibited βL activity, as it was shown to catalyze the hydrolysis of benzylpenicillin 1s (Figure 1). The Zn²⁺

M. Beaumet, S. Wiorek, J.-P. Mahy, W. Ghattas
Institut de Chimie Moléculaire et des Matériaux d'Orsay (ICMMO)
UMR 8182 CNRS - Université Paris-Saclay
Orsay 91405 Cedex, France
E-mail: wadih.ghattas@cnrs.fr

<figure><img src="image_3.png" /></figure>

© 2025 The Author(s). European Journal of Inorganic Chemistry published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
<figure><img src="image_4.png" /></figure>

<figure><img src="image_5.png" /><figcaption>**Scheme 1.** Hydrolysis of β-lactam substrates (s) into the corresponding products (p) catalyzed by a βL.</figcaption></figure>

coordination sphere in 2c is thought to include a hydroxyl group with a pKa of 7.9, justifying its supposed role in the nucleophilic attack on the carbonyl group of the β lactam, ultimately hydrolyzing benzylpenicillin 1s. While the product was characterized by ¹H NMR, the kinetic parameters of this reaction were determined using the pH-stat technique. These studies made it possible to determine a hydrolysis second-order rate constant of 4.1 × 10⁻² M⁻¹s⁻¹ (calculated TOF = 2.3 s⁻¹) and to propose the formation of a reaction intermediate (1i; i, standing for intermediate) that was stabilized by the coordination of the forming carboxylate group, while the ring tension facilitated the cleavage of the C²–N¹ bond, leading to the opening of the β lactam (Scheme 2).

## 2.2. Pyrazolylborate Complexes

In 1999, Vahrenkamp's team prepared Zn²⁺ complexes of 3 arylpyrazolyl borate, such as 3c and 4c (Figure 2), and tested their catalytic activities in the hydrolysis of different groups including amides.[19] Although these trials were inconclusive, the authors repeated the

experiments in 2005[20] by using β lactams as substrates. They determined a maximum rate constant of 0.57 and 0.13 M⁻¹s⁻¹ for complexes 3c and 4c, respectively, based on the shifts of the ¹H NMR signals corresponding to the benzylic protons of substrate monobactam 2s (Figure 1) upon hydrolysis to yield β amino acid product 2p. The isopropyl substituents at the *para*-position of the phenyl groups of the ligand in 4c were proposed to hinder the access of 2s to the Zn²⁺-bound hydroxyl group that was thought to be responsible for the catalysis thus explaining the slower reaction with this complex. The authors also obtained crystal structures that implied that the hydroxyl group of the complexes could be substituted by the carboxyl groups of β amino acids. One structure indeed shows 2p bound instead of the hydroxyl group of complex 3c (Figure 3A). These studies prove that the forming carboxylate group can bind to Zn²⁺ and thus further support the idea that the reaction intermediate is stabilized through coordination. While N-substituted lactams such as 1s reacted to yield the corresponding β-amino acids, NH-containing lactams reacted in an acid-base reaction to yield the corresponding β lactamide complexes and water that is, without hydrolysis (see example in Figure 3B).

## 2.3. Mononuclear: Model Complexes Versus MβLs

The study of mononuclear complexes suggests that the hydrolysis reaction is initiated by the nucleophilic attack of the β lactam

<figure><img src="image_6.png" /><figcaption>**Figure 1.** Structures of the substrates used in the studies of model complexes of MβLs. 1s, 7s and 8s are penicillins, 3s and 6s are cephalosporins and 2s is a monobactam, 4s is a carbapenem and 5s is a penicillin sulfone.</figcaption></figure>

<figure><img src="image_7.png" /><figcaption>**Figure 2.** Different complexes used to mimic mononuclear MβLs.</figcaption></figure>
<figure><img src="image_8.png" /></figure>

<figure><img src="image_9.png" /><figcaption>**Scheme 2.** Hydrolysis of **1s** catalyzed by **2c** showing the proposed reaction intermediate **1i**.[20]</figcaption></figure>

by a coordinated hydroxyl group. The reaction could be further facilitated because the formed intermediate can be stabilized by coordination to Zn²⁺. On the other hand, the study of class B2 MβLs also suggests the possible coordination of the reaction intermediate and possibly the substrate to the Zn²⁺ of the active site. However, a water molecule involved in two hydrogen bonds with an aspartic acid residue and with a histidine residue is thought to be responsible of the hydrolysis of β lactam substrates (**Scheme 3**). This water molecule is thus nucleophilic but is not coordinated by Zn²⁺.[21,22] Most existing model complexes were synthesized before comprehensive structural and mechanistic data on the enzymes became available, explaining the substantial differences between these models and the mononuclear MβLs they aim to mimic. Activity comparison between complexes and activity comparison between enzymes and complexes are difficult because of the different experimental conditions and the different substrates that were used. It is noteworthy however, that enzymes are far more active than the reported complexes. For example, a typical class B2 MβL such as that of *Aeromonas hydrophila* shows a TOF of 1200 s⁻¹ with imipenem **4s** that is, a semi-synthetic substrate.[23] New model complexes that incorporate elements deriving from the latest findings from enzyme research are thus needed (vide infra, 4.), as they are expected to serve as more accurate mimics.[24,25]

<figure><img src="image_10.png" /><figcaption>**Scheme 3.** Mechanism proposed for the hydrolysis of β lactams catalyzed by class B2 MβLs.</figcaption></figure>

## 3. Biomimetic Complexes of Dinuclear Metallo-β-Lactamases

### 3.1. Pyrazolamine Complexes

Meyer et al. synthesized numerous dinuclear zinc complexes in the 1990s, and, in 2005, they reported the βL activity of complexes **5c–8c** (Figure 4A).[26] In particular, the hydrolysis of benzylpenicillin **1s** was studied using infrared spectroscopy by following the shift of the band associated with the elongation of the C²=O bond at 1768 cm⁻¹. Complex **7c** showed no activity, and complex **8c** showed a lower activity than that of zinc perchlorate, while complexes **5c** and **6c** were more active, **5c** being the most active one. ¹³C NMR in acetone-d₆/D₂O mixture allowed to better understand the interaction between the substrate and the complexes.[27,28] Indeed, a shift in the signal associated to C⁸ was observed upon the addition of **1s** to a solution of complex **6c** (δ C⁸ (1s) = 163.8 ppm vs. δ C⁸ (1s + 6c) = 166.7 ppm), which led the authors to suggest that **1s** bound to one or both zinc cations though its carboxyl group. They further indicated that the coordination of the substrate required the decoordination either of one of the amine ligands or of the µ hydroxo ligand. In the former case, the µ hydroxo ligand could thereafter react with the zinc-bound substrate, leading to its hydrolysis. The alkyl chains bearing the dimethylamine ligands are longer in **5c**, thus are more flexible, which should facilitate their substitution by the substrate

<figure><img src="image_11.png" /><figcaption>**Figure 3.** A) Ortep graphical representation of the crystal structure of β-amino acid 2p bound to the core of 3c via its carboxyl group. All hydrogen atoms were omitted for the sake of more clarity. B) Similar representation of β propiolactamide bound to the core of 3c. A cocrystallized acetonitrile molecule was also omitted.</figcaption></figure>
<figure><img src="image_12.png" /></figure>

<figure><img src="image_13.png" /><figcaption>**Figure 4.** A) Dinuclear zinc complexes of pyrazolamine-like ligands developed by Meyer et al. to mimic MβLs and proposed reaction intermediate 2i. B) Left, chemdraw drawing of **9c** and right, ortep graphical representation of the crystal structure of sulbactam **5s** bound via its carboxyl group to both Zn²⁺ of **9c** by substituting the acetonitrile ligand. All hydrogen atoms, counter ions and solvent molecules were omitted for the sake of more clarity.</figcaption></figure>

and lead to the observed higher activity. Furthermore, the analysis of the crystal structures of the complexes made it possible to measure the inter-zinc distances in each of the four complexes: Zn···Zn = 3.61; 3.47; 4.41 and 4.15 Å for **5c–8c**, respectively. The current state of the art allows us to compare these distances to those observed in the structures of MβLs. These vary between 3.1 and 3.8 Å, implying that complexes **5c** and **6c** are better structural mimics of MβLs than complexes **7c** and **8c**. Such inter-zinc distances not only allow the coordination of the substrate to one zinc cation via its carboxylic acid function but also allow the judicious positioning of the forming carboxylate group for its stabilization by coordination with the second zinc cation (see proposed intermediate **2i** in Figure 4A). The most active complex, **5c**, indeed combines flexible ligands with an adequate inter-zinc distance. The latter case, that is, substrate binding, requires coordination of the µ hydroxo ligand, would lead to an inactive complex as it lacks the hydroxyl group responsible for the hydrolysis. Furthermore, the crystal structure of the product of the reaction of **9c** and **5s** (Figure 4B) revealed that indeed the substrate could bridge the two cations with its carboxylate function, but

that led to the positioning of the β-lactam amide moiety relatively far from the di-zinc site. Therefore, an additional hydroxyl ligand would not be able to attack the β-lactam.[28]

## 3.2. Phenolamine Complexes

In the early 2000s, Lippard's team synthesized several dinuclear zinc complexes and used them as catalysts for the hydrolysis of β lactams.[29–31] They described complexes **10c-12c** (Figure 5) that were produced starting from ligands comprising a phenol center substituted by different coordinating groups such as ethylene diamine and ethylene amino pyridine. The coordination sphere of the Zn²⁺ cations was completed by a methanolate or a nitrate that was shown to get substituted by a µ hydroxo ligand in the presence of water. The complexes were characterized by elemental analysis, ¹H NMR and their molecular structures were determined by XRD. The different inter-zinc distances Zn···Zn = 3.10; 3.29, and 3.39 Å were measured for the **10c-12c**, respectively. Also, the binding mode of benzylpenicillin **1s** and cefalotin **3s** (Figure 1) with the different complexes was studied by
<figure><img src="image_14.png" /></figure>

<figure><img src="image_15.png" /><figcaption>Figure 5. Dinuclear Zn²⁺ phenolamine complexes mimics of MβLs.</figcaption></figure>

¹³C NMR and IR spectroscopy. ¹³C NMR performed in a 1:1 acetone-d₆:DMSO-d₆ mixture revealed that the signal assigned to C⁸ of the carboxyl group of 1s shifted from 171.7 ppm, in its free state, to 174.1 ppm in the presence of complexes. Similarly, in DMSO-d₆, the signal of the C⁹ carbon of the carboxylate group of the cefalotin shifted from 164.3 ppm, in its free state, to 166.9 ppm in the presence of complexes. Moreover, IR spectroscopy analysis showed that in the absence and in the presence of complex, the band corresponding to the carboxylate (C⁸OO⁻) of 1s shifted from 1621 to 1638 cm⁻¹ while that assigned to the carboxylate (C⁹OO⁻) of 3s shifted from 1617 to 1630 cm⁻¹. On the other hand, after adding complexes 10c–12c to the substrate solutions, neither the signals corresponding to the C² carbons nor those corresponding to the C²O bonds of 1s and 3s showed any variation in their respective ¹³C NMR or IR spectra. These results support the hypothesis that penicillins and cephalosporins bind to Zn²⁺ cations through their carboxylate group but not through their amide group.

The authors then determined the kinetics of the hydrolysis of cephalosporins when catalyzed by **10c-12c** complexes using UV-visible spectroscopy. To this end, nitrocefin **6s** (Figure 1) was used as a substrate, as its hydrolysis causes a shift in its maximum absorbance wavelength (nitrocefin $\lambda_{max}$ = 390 nm vs. hydrolyzed nitrocefin $\lambda_{max}$ = 486 nm) allowing kinetic follow-up by UV-Vis spectrophotometry. The three complexes exhibited a comparable reactivity, as demonstrated by the observed catalytic rate constants ($k_{obs}$ = 4.2 × 10⁻³, 6.0 × 10⁻³, and 13.7 × 10⁻³ min⁻¹ for **10c-12c**, respectively).

Mugesh's group also prepared several mono- and dinuclear zinc complexes.[32,33] Here, only dinuclear phenolamine complexes **13c** and **14c** are presented because they are good mimics of MβLs, as their structures show interzinc distances of Zn···Zn = 3.35 and 3.39 Å, respectively (Figure 5). Additionally, each of these complexes contain a water molecule coordinated to one of the Zn²⁺

and a bridging acetate ligand, which is considered a mimic of glutamate or aspartate ligands. One of the zinc cations in binuclear MβLs is indeed bound by such an anionic amino acid that is conserved across classes B1 and B3, vide infra. The hydrolysis of oxacillin 7s (Figure 1) in the presence of these complexes was confirmed by ¹H NMR analysis based on the appearance of the signal corresponding to the forming N¹H proton. Initial hydrolysis rates of 4.12 and 4.79 µM min⁻¹ were determined by HPLC when using **13c** or **14c**, respectively.

More recently, Abbehausen's team designed and prepared Zn²⁺ dinuclear complexes.[34,35] Among these, bis-phenolethylene-diamine complex **15c** stands-out with an interzinc distance of Zn···Zn = 3.12 Å (Figure 5). The coordination sphere of each Zn²⁺ is composed of two nitrogen atoms from the ethylenediamine fragment and two oxygen atoms, one from of the phenolate and the other from additional acetate ligands. In the presence of the **15c**, an initial hydrolysis rate of nitrocefin **6s** (Figure 1) of 1.01 × 10⁻⁸ M s⁻¹) was determined by UV-visible spectrophotometry. The interaction of **15c** with the carboxylate of another substrate, that is, amoxicillin **8s** (Figure 1), was confirmed by ¹H NMR in d₆-DMSO following the shift of the signal assigned to C⁴H (δ C⁴H (8s) = 4.72 ppm versus δ C⁴H (8s + 15c) = 4.54 ppm).

### 3.3. Dinuclear Model Complexes vs MβLs

Here also, the model complexes of dinuclear MβLs were synthesized before detailed findings on the enzymes became available. Studies of the model complexes suggest that the coordination of the substrate to Zn²⁺ is followed by its attack by a coordinated hydroxyl group, bridging the Zn²⁺ cations. The findings of the study of Class B1[36] and B3 MβLs[37] agree with these conclusions but reveal that the reactive hydroxyl group is further involved in a hydrogen bond with an acidic residue of the active site and is thus more nucleophilic than that of the model complexes
<figure><img src="image_16.png" /></figure>

(Scheme 4).[38,39] New more accurate dinuclear model complexes are thus also needed (vide infra, 4.).

### 3.4. Outlook to Enhanced Biomimicry

MβL mimics are functional model complexes that replicate the catalytic activity of MβLs. They comprise a hydroxyl group coordinated to the Zn²⁺, however, in none of these complexes the hydroxyl group was made more nucleophilic through its involvement in a hydrogen bond with elements of the first or the second coordination sphere of Zn²⁺, as observed in mononuclear and dinuclear MβLs. Obtaining such complexes is therefore of utmost importance for studying the impact of the hydrogen bonding on the activity. Such complexes may also be adapted to study other enzymes. For example, they could be employed to study the impact of hydrogen bonding on the reactivity of high valent metal-oxygen species of iron-containing oxygenases. Indeed, recent studies of new mimics of their active sites have revealed that their reactivity can be modulated by involving the metal-hydroperoxo intermediate in a hydrogen bond.[40–43]

In addition, both B1 and B3 MβLs comprise in their active sites two Zn²⁺ for which one binding site typically involves three histidine residues, whereas the second one involves three amino acids,[44] typically two histidine residues and an acidic residue (glutamate aspartate).[45] In B1 enzymes, however, a cysteine residue may contribute to the coordination by substituting one of the two histidine residues of the second site.[46] Most model complexes reported so far comprise symmetric positively charged sites, as most ligands are neutral amines. As highlighted above, the negatively charged substrate binds by bridging both positively charged sites (see Figure 4B), leaving no possibility for hydroxyl binding and positioning the lactam away from the zinc centers. In contrast, non-symmetric sites, with a first amine-rich site and a second bearing anionic ligands such as carboxylates or thiolates that reduce its positive charge, may thus favor coordination of the negatively charged substrate at the first zinc site. This is in harmony with the structural and mechanistic insights gathered on enzymes (see Scheme 4).

In addition, a judicious number of ligands in each site and inter Zn²⁺ distance are important factors that lead to strong binding of Zn²⁺ and enable the coordination of substrates and reaction intermediates. By simulating and elucidating the effect of different ligands on substrate binding, modern molecular modeling tools,

<figure><img src="image_17.png" /><figcaption>**Scheme 4.** Catalytic mechanism of β lactam hydrolysis by class B1 and B3 MβLs.</figcaption></figure>

particularly molecular dynamics, may aid in the development of more efficient model complexes.[47–49]

Current MβL mimics neglect such electronic and structural characteristics that are certainly important to achieve better βL activity. New model complexes that reflect recent findings on enzymes and thus include varying numbers of ligands at nonsymmetrically charged sites are necessary to elucidate the role of each binding site. Here too, such complexes may also be adapted to study other enzymes. For example, dinuclear copper-containing oxygenases comprise two nonsymmetrically charged copper binding sites with different ligands.[50,51] Current model complexes do not replicate these features and so cannot reveal each center's role in the catalysis of oxygen incorporation. New complexes that do replicate them might enable this identification.[52] In fact, these new models might corroborate the conclusions of mutation studies, which indicated that one site serves to transfer electrons to the second site, thought to be the catalytic site.[53]

Since β-lactamases continue to evolve[54] in response to newly developed antibiotics,[55] model complexes can be readily adapted to reflect emerging variants and thus would be powerful tools for mechanistic studies. Knowledge gained from these complexes may inform the development of novel, crucial antibiotics and MβL inhibitors.

### Conflict of Interest

The authors declare no conflict of interest.

**Keywords:** bioinorganic chemistry · biomimetic chemistry · hydrolase · metallo-β-lactamase · zinc complexes

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Manuscript received: April 11, 2025

Revised manuscript received: August 29, 2025

Version of record online: September 17, 2025