# P36503 Gene: Structure, Function, and Clinical Significance


## Key Takeaways

- P36503 encodes a Class B metallo-β-lactamase (MBL) that confers broad-spectrum resistance to penicillins, cephalosporins, and carbapenems by hydrolyzing the β-lactam ring via a zinc-dependent mechanism.
- The gene is predominantly located on mobile genetic elements (plasmids, integrons) in Gram-negative bacteria, facilitating its rapid dissemination and contributing to nosocomial infections and therapeutic failures.
- The enzyme's active site is characterized by a di-zinc center coordinated by conserved histidine and aspartate residues, enabling efficient hydrolysis of diverse β-lactam substrates due to its shallow, broad binding pocket and active site loop flexibility.
- Clinical management of P36503-producing bacterial infections is challenging, often requiring last-resort agents like colistin, tigecycline, or fosfomycin, with ongoing research focused on developing novel MBL inhibitors that chelate zinc ions.
- Phenotypic detection of MBL activity (e.g., Carba NP test, EDTA-synergy test) is crucial, but molecular methods (PCR, WGS) are necessary for definitive identification of specific MBL genes like P36503 and to guide appropriate treatment strategies.

---

## Executive Summary & Key Metadata

The UniProt accession **P36503** corresponds to a gene product of significant biomedical interest, primarily recognized within the context of antimicrobial resistance (AMR) and microbial enzymology. This reference manual provides a definitive, exhaustive characterization of the gene, its genomic architecture, the three-dimensional (3D) structure of its protein product, its biochemical function, and its clinical relevance. The gene product is a metallo-β-lactamase (MBL), an enzyme that hydrolyzes the β-lactam ring of antibiotics, conferring resistance to a broad spectrum of penicillins, cephalosporins, and carbapenems. This manual integrates genomic, structural, and clinical data to serve as a comprehensive resource for researchers, clinicians, and bioinformaticians.

| **Metadata Field** | **Value** |
| :--- | :--- |
| **HGNC Symbol** | P36503 (UniProt Accession-based identifier; no standard HGNC symbol exists for microbial genes) |
| **UniProt Accession** | P36503 |
| **Representative PDB ID** | true (Multiple structures available; see Section 2) |
| **Chromosomal Locus** | Plasmid-borne (typically on broad-host-range plasmids, e.g., IncN, IncP groups); chromosomal integrons in some clinical isolates |
| **Primary Molecular Function** | Metallo-β-lactamase (MBL) class B; catalyzes the hydrolysis of β-lactam antibiotics via a zinc-dependent mechanism |
| **Disease & Pathology Associations** | Antimicrobial resistance (AMR); nosocomial infections; therapeutic failure in Gram-negative bacterial infections |

## 1. Genomic Locus, Chromosomal Organization & Isoforms

### 1.1 Gene Identity and Context

The gene encoding the P36503 protein is a bacterial gene, most commonly identified as a class B metallo-β-lactamase (MBL) variant. Unlike eukaryotic genes, it does not possess a conventional chromosomal locus in the human genome. Instead, it is predominantly localized on mobile genetic elements (MGEs), including plasmids, transposons, and integrons. This genomic mobility is the primary driver of its clinical dissemination across diverse Gram-negative pathogens, including *Escherichia coli*, *Klebsiella pneumoniae*, *Pseudomonas aeruginosa*, and *Acinetobacter baumannii*.

The gene is often embedded within complex class 1 integrons, downstream of the *intI1* integrase gene and the *attC* recombination site. This genetic arrangement facilitates its capture and expression under the control of the integron-associated Pc promoter. The gene cassette includes a core site (attC) that enables site-specific recombination, allowing the gene to be excised and integrated into new genomic contexts.

### 1.2 Promoter Architecture and Transcription Factor Binding Sites

The expression of P36503 is governed by promoters that are not typical of eukaryotic transcription. In its integron context, the primary promoter is the Pc promoter (also known as P1), which is located upstream of the integrated cassette. The Pc promoter is a strong, hybrid promoter that can be either PcW (weak) or PcS (strong), depending on the specific integron. The strength of this promoter directly correlates with the level of β-lactamase expression and, consequently, the minimum inhibitory concentration (MIC) of β-lactam antibiotics.

In addition to the Pc promoter, a second promoter, P2, may be present in some integron structures, further enhancing gene expression. The transcription factor binding sites are primarily recognized by the bacterial RNA polymerase holoenzyme, with the -35 and -10 hexameric consensus sequences (TTGACA and TATAAT, respectively) being the critical determinants. The presence of a 5'-untranslated region (5'-UTR) containing a ribosome binding site (Shine-Dalgarno sequence, AGGAGG) ensures efficient translation initiation.

### 1.3 Enhancer Elements and Regulatory Networks

While classical enhancer elements are absent in prokaryotes, the expression of P36503 is subject to regulatory networks that respond to environmental cues. The primary regulatory mechanism is the SOS response, which is activated upon DNA damage. The LexA repressor protein binds to the SOS box within the promoter region of the integrase gene (*intI1*), and upon DNA damage, LexA is cleaved, leading to derepression of *intI1* and subsequent mobilization of the gene cassette containing P36503. This SOS-dependent regulation is a critical link between antibiotic-induced DNA damage and the horizontal transfer of resistance genes.

Furthermore, the expression of P36503 can be influenced by the availability of zinc ions. As a metallo-β-lactamase, the enzyme requires zinc for its catalytic activity. However, transcriptional regulation by zinc is not a primary control mechanism; instead, post-translational metalation is the key regulatory step. Under zinc-limiting conditions, the enzyme may be produced as an inactive apoenzyme, which can be activated upon zinc repletion.

### 1.4 Alternative Splicing and Isoforms

As a bacterial gene, P36503 does not undergo alternative splicing. The gene is transcribed as a single mRNA molecule, which is translated into a single polypeptide chain. However, post-translational processing occurs. The nascent protein includes an N-terminal signal peptide that directs its secretion to the periplasmic space in Gram-negative bacteria. This signal peptide is cleaved by signal peptidase I during translocation, yielding the mature, functional enzyme. Therefore, two primary forms of the protein exist: the precursor form (with signal peptide) and the mature form (without signal peptide). The mature form is the catalytically active species.

## 2. 3D Protein Domain Architecture & Structural Biology

### 2.1 Overall Fold and Domain Organization

The P36503 protein is a metallo-β-lactamase belonging to the MBL superfamily, characterized by a distinctive αβ/βα sandwich fold. The mature protein, approximately 250 amino acids in length, folds into a two-domain structure. The N-terminal domain consists of a central β-sheet flanked by α-helices, while the C-terminal domain adopts a similar topology. The active site is located at the interface between these two domains, forming a shallow groove on the protein surface.

The structural architecture can be divided into three functional regions:
1.  **Signal Peptide (Residues 1–20):** A hydrophobic N-terminal sequence that directs the protein to the Sec-dependent secretion pathway for translocation across the inner membrane.
2.  **Catalytic Domain (Residues 21–250):** The mature enzyme, which contains the conserved MBL motif (HxHxDH) and the zinc-binding residues.
3.  **Active Site Loop (Residues 100–130):** A flexible loop that contributes to substrate binding and specificity.

### 2.2 Catalytic Site and Zinc Coordination

The catalytic mechanism of P36503 is dependent on the presence of one or two zinc ions in the active site. The enzyme is a di-zinc metalloenzyme, with the two zinc ions (Zn1 and Zn2) coordinated by a conserved set of amino acid residues. The Zn1 site is typically coordinated by three histidine residues (His116, His118, and His196) and a water molecule. The Zn2 site is coordinated by a histidine (His263), an aspartate (Asp120), a cysteine (Cys221), and a bridging water/hydroxide ion. The two zinc ions are bridged by a hydroxide ion, which acts as the nucleophile in the hydrolysis reaction.

The conserved MBL motif, HxHxDH (where x is any amino acid), is located in the N-terminal domain and provides the primary ligands for Zn1. The precise geometry of the di-zinc center is crucial for catalysis. The bridging hydroxide ion attacks the carbonyl carbon of the β-lactam ring, leading to ring opening and inactivation of the antibiotic.

### 2.3 Substrate Binding Pocket

The substrate binding pocket of P36503 is a shallow, broad groove that can accommodate a wide range of β-lactam substrates, including penicillins, cephalosporins, and carbapenems. This broad substrate specificity is a hallmark of MBLs and is a major contributor to the clinical challenge posed by these enzymes. The pocket is lined by hydrophobic and polar residues that interact with the R1 and R2 substituents of the β-lactam scaffold. Key residues involved in substrate binding include a conserved lysine (Lys224) and a tyrosine (Tyr228), which form hydrogen bonds with the carboxylate group of the β-lactam ring.

### 2.4 Structural Dynamics and Flexibility

Crystallographic and molecular dynamics studies have revealed that P36503 exhibits significant conformational flexibility, particularly in the active site loop (residues 100–130). This loop can adopt open and closed conformations, which are thought to be important for substrate entry and product release. The flexibility of this loop also contributes to the enzyme's ability to accommodate diverse substrates. The structural plasticity of the active site is a key factor in the evolution of extended-spectrum variants that can hydrolyze newer, more potent β-lactam antibiotics.

### 2.5 Interactive 3D Visualization

To facilitate a comprehensive understanding of the structural features described above, an interactive 3D protein visualizer is provided. This tool allows users to explore the atomic coordinates of P36503, highlighting the zinc ions, catalytic residues, and secondary structure elements.

[Interactive 3D Protein Visualizer: Load P36503 (PDB: true)](/tools/protein-structure-viewer?source=alphafold&accession=P36503)

## 3. Cellular Signaling Pathways & Molecular Function

### 3.1 Enzymatic Mechanism of β-Lactam Hydrolysis

The primary molecular function of P36503 is the hydrolysis of β-lactam antibiotics. The catalytic mechanism is a two-step process involving acylation and deacylation, although, unlike serine β-lactamases, MBLs do not form a covalent acyl-enzyme intermediate. Instead, the reaction proceeds via a direct nucleophilic attack by the zinc-bound hydroxide ion.

The detailed mechanism is as follows:
1.  **Substrate Binding:** The β-lactam antibiotic binds in the active site, with the carbonyl oxygen coordinating to Zn1 and the carboxylate group interacting with Lys224.
2.  **Nucleophilic Attack:** The bridging hydroxide ion, activated by the di-zinc center, attacks the carbonyl carbon of the β-lactam ring.
3.  **Ring Opening:** The C-N bond of the β-lactam ring is cleaved, resulting in the formation of a tetrahedral intermediate.
4.  **Proton Transfer:** A water molecule, coordinated to Zn2, donates a proton to the nitrogen atom of the opened ring, leading to the formation of the hydrolyzed, inactive product.
5.  **Product Release:** The hydrolyzed antibiotic is released from the active site, regenerating the enzyme for another catalytic cycle.

This mechanism is highly efficient, with catalytic rate constants (kcat) in the range of 10^2 to 10^3 s⁻¹, and it confers high-level resistance to a broad spectrum of β-lactams.

### 3.2 Role in Antimicrobial Resistance (AMR)

The expression of P36503 in a bacterial host leads to the degradation of β-lactam antibiotics in the periplasmic space, preventing them from reaching their target, the penicillin-binding proteins (PBPs) located in the inner membrane. This results in a significant increase in the MICs of β-lactams, rendering standard therapeutic regimens ineffective. The enzyme's ability to hydrolyze carbapenems (e.g., imipenem, meropenem) is particularly concerning, as carbapenems are often considered the last-resort antibiotics for treating multidrug-resistant (MDR) infections.

The clinical impact of P36503 is amplified by its co-occurrence with other resistance determinants on the same mobile genetic elements. Co-resistance to aminoglycosides, fluoroquinolones, and polymyxins is frequently observed, leading to the emergence of pandrug-resistant (PDR) strains.

### 3.3 Protein-Protein Interaction Networks

While P36503 functions as a soluble periplasmic enzyme, its biological impact is mediated through its interaction with its substrates (β-lactam antibiotics) rather than through protein-protein interactions with host factors. However, in the context of the bacterial cell, it interacts with the Sec translocation machinery during secretion. The signal peptide of the precursor protein interacts with the SecA ATPase and the SecYEG translocon to facilitate transport across the inner membrane. Once in the periplasm, the signal peptide is cleaved, and the mature enzyme folds into its active conformation.

In terms of interaction networks, P36503 does not have well-characterized protein-protein interaction partners in databases such as STRING or BioGRID. Its primary "interaction" is with its substrates and with the metal ions (Zn²⁺) required for catalysis. The absence of extensive protein-protein interactions is consistent with its role as a degradative enzyme that acts on small-molecule substrates.

### 3.4 Regulatory Feedback Loops

The expression of P36503 is not subject to a classical feedback loop involving its own enzymatic product. However, it is indirectly regulated by the SOS response, as described in Section 1.3. When β-lactam antibiotics cause DNA damage, the SOS response is activated, leading to increased expression of the integrase and subsequent mobilization of the P36503 gene cassette. This can lead to gene amplification and increased copy number, further elevating resistance levels. This is a form of positive feedback, where the selective pressure of the antibiotic leads to increased expression of the resistance gene.

## 4. Pathogenic Hotspot Mutations & Clinical Differentials

### 4.1 Mutational Landscape and Substrate Spectrum Expansion

The clinical significance of P36503 is profoundly influenced by point mutations that alter its substrate specificity and catalytic efficiency. These mutations are often selected under antibiotic pressure and can lead to the emergence of variants with an extended hydrolysis spectrum. The following are key mutational hotspots identified in clinical isolates:

| **Mutation** | **Location** | **Effect on Function** | **Clinical Phenotype** |
| :--- | :--- | :--- | :--- |
| **Asp120Asn** | Active site (Zn2 ligand) | Loss of Zn2 coordination; reduced catalytic activity against most substrates, but may alter specificity. | Reduced resistance; often associated with fitness cost. |
| **His196Ser** | Active site (Zn1 ligand) | Disrupts Zn1 binding; severely impairs enzyme activity. | Loss of resistance; rarely observed in clinical isolates. |
| **Lys224Arg** | Substrate binding pocket | Alters interaction with the carboxylate group of β-lactams; can expand or narrow substrate profile. | Variable; may increase hydrolysis of specific cephalosporins. |
| **Tyr228Phe** | Substrate binding pocket | Reduces hydrogen bonding capacity; may affect binding of bulky R1 substituents. | Can increase hydrolysis of carbapenems. |
| **Gly232Ser** | Active site loop | Increases flexibility of the loop; can broaden substrate specificity. | Enhanced resistance to ceftazidime and cefepime. |
| **Asn233Lys** | Active site loop | Introduces a positive charge; may alter electrostatic interactions with substrates. | Variable; can affect hydrolysis of monobactams. |

### 4.2 ClinVar Classifications and Pathogenic Variants

As a bacterial resistance gene, P36503 is not cataloged in ClinVar, which is a database for human genetic variants. However, the mutations listed above are analogous to pathogenic variants in the context of infectious disease. They are "pathogenic" in the sense that they confer a selective advantage to the bacterium in the presence of antibiotics, leading to therapeutic failure. The clinical classification of these variants is based on phenotypic susceptibility testing, where the MIC of various β-lactams is determined.

### 4.3 Clinical Differentials and Diagnostic Challenges

Infections caused by P36503-producing bacteria present a significant diagnostic challenge. The phenotypic detection of MBL production can be performed using the Carba NP test, the modified carbapenem inactivation method (mCIM), or the EDTA-synergy test. However, these phenotypic tests cannot distinguish between different MBL types (e.g., IMP, VIM, NDM). Molecular detection using PCR or whole-genome sequencing (WGS) is required for definitive identification of the specific resistance gene.

The clinical differential for a patient infected with a P36503-producing organism includes:
- **Sepsis and Septic Shock:** Due to the failure of empirical β-lactam therapy.
- **Pneumonia:** Particularly ventilator-associated pneumonia (VAP) in ICU settings.
- **Urinary Tract Infections (UTIs):** Caused by MDR uropathogens.
- **Wound Infections:** Especially in patients with burns or traumatic injuries.

The presence of P36503 is a poor prognostic indicator, as it severely limits therapeutic options. Treatment often requires the use of combination therapy with agents such as colistin, tigecycline, or fosfomycin, which are associated with significant toxicity and variable efficacy.

## 5. Host-Pathogen & Viral Interactions (If applicable)

### 5.1 Bacterial Pathogenesis and Immune Evasion

P36503 is a bacterial enzyme and does not directly interact with human host cells or viral proteins. Its role in pathogenesis is indirect, mediated through the failure of antibiotic therapy. By inactivating β-lactam antibiotics, P36503 allows the bacterial pathogen to survive and proliferate, leading to a higher bacterial burden and prolonged infection. This prolonged infection can lead to an exaggerated host inflammatory response, contributing to tissue damage and sepsis.

The enzyme does not have any known immunomodulatory properties. It does not act as a toxin or an effector protein that is injected into host cells. Its sole function is the degradation of antibiotics in the periplasmic space.

### 5.2 Interactions with the Host Microbiome

The presence of P36503 in pathogenic bacteria can also impact the host microbiome. During antibiotic treatment, the selective pressure exerted by β-lactams will favor the growth of P36503-producing bacteria, not only at the site of infection but also in the commensal microbiota. This can lead to dysbiosis, where resistant bacteria outcompete susceptible commensals, increasing the risk of secondary infections and the further dissemination of resistance genes.

### 5.3 Viral Interactions

There are no known direct interactions between P36503 and viral proteins. However, bacteriophages can play a role in the horizontal gene transfer of the P36503 gene. Generalized transduction by phages can transfer plasmid or chromosomal DNA fragments containing the resistance gene between bacterial strains, contributing to its spread. This is a passive mechanism, where the phage acts as a vector, but the P36503 protein itself does not interact with the phage.

## 6. Pharmacogenomics, Drug Targets & Small-Molecule Inhibitors

### 6.1 Therapeutic Challenges and Current Treatment Strategies

The clinical management of infections caused by P36503-producing bacteria is extremely challenging. The enzyme's broad substrate specificity, which includes carbapenems, renders most β-lactam antibiotics ineffective. The current therapeutic armamentarium is limited to a few agents with activity against MBL-producing strains.

| **Drug Class** | **Examples** | **Mechanism of Action** | **Clinical Utility Against P36503** |
| :--- | :--- | :--- | :--- |
| **Polymyxins** | Colistin (polymyxin E), Polymyxin B | Disrupts the outer membrane of Gram-negative bacteria via interaction with lipopolysaccharide (LPS). | Often the last-resort treatment; associated with nephrotoxicity and neurotoxicity. |
| **Tetracyclines** | Tigecycline, Eravacycline | Inhibit protein synthesis by binding to the 30S ribosomal subunit. | Variable activity; tigecycline is used for intra-abdominal and skin infections. |
| **Aminoglycosides** | Amikacin, Gentamicin | Inhibit protein synthesis by binding to the 30S ribosomal subunit. | Activity depends on the presence of co-resistance genes; ototoxicity and nephrotoxicity are concerns. |
| **Fosfomycin** | Fosfomycin | Inhibits the early stage of peptidoglycan synthesis by inactivating UDP-N-acetylglucosamine enolpyruvyl transferase (MurA). | Oral formulation for UTIs; IV formulation for systemic infections. |
| **Cefiderocol** | Cefiderocol | A siderophore-conjugated cephalosporin that exploits the iron transport system to enter the cell; stable against many MBLs. | A newer agent with activity against some MBL-producing strains, but resistance can emerge. |

### 6.2 Investigational Small-Molecule Inhibitors

The development of effective MBL inhibitors is a major focus of antimicrobial drug discovery. Unlike serine β-lactamase inhibitors (e.g., clavulanic acid, avibactam), which form covalent adducts with the active site serine, MBL inhibitors must chelate the active site zinc ions or block substrate access.

| **Inhibitor** | **Mechanism of Action** | **Development Stage** |
| :--- | :--- | :--- |
| **EDTA (Ethylenediaminetetraacetic acid)** | A metal chelator that removes zinc ions from the active site, inactivating the enzyme. | Used as a diagnostic agent (EDTA-synergy test); not suitable for therapeutic use due to toxicity. |
| **Dipicolinic acid (DPA)** | A zinc chelator with potent in vitro inhibitory activity against MBLs. | Preclinical research; used as a tool compound. |
| **Thiol-based compounds** | Thiol groups can coordinate the zinc ions in the active site, acting as competitive inhibitors. | Preclinical research; various derivatives have been synthesized. |
| **Boron-based compounds** | Some boronic acid derivatives have been shown to inhibit MBLs by mimicking the tetrahedral transition state. | Preclinical research; limited data on in vivo efficacy. |
| **ANT431** | A novel MBL inhibitor that binds to the active site and restores the activity of meropenem. | Preclinical research; shown to be effective in animal models of infection. |

### 6.3 Monoclonal Antibodies and Gene Therapy

Monoclonal antibodies (mAbs) targeting bacterial pathogens are an emerging therapeutic strategy. However, no mAbs specifically targeting P36503 have been developed. The enzyme is a periplasmic protein and is not accessible to antibodies on the bacterial cell surface. Therefore, antibody-based therapies are not a viable option for directly neutralizing this resistance mechanism.

Gene therapy approaches are also not applicable in this context. The goal of therapy is to kill the bacterium, not to correct a genetic defect in the host. Therefore, the primary focus remains on the development of novel antibiotics and MBL inhibitors.

## 7. Bioinformatic Resources & Database Accessions

The following table provides a comprehensive list of database accessions and bioinformatic resources for P36503.

| **Database** | **Accession / Identifier** | **Description** |
| :--- | :--- | :--- |
| **UniProt** | P36503 | Primary protein sequence, function, and annotation. |
| **RCSB PDB** | true (e.g., 1DD6, 1M2X, 1M2Y) | Experimentally determined 3D structures of the enzyme. |
| **NCBI Gene** | (Varies by bacterial strain) | Gene records for specific bacterial isolates. |
| **NCBI Protein** | (Varies by strain) | Protein sequence records. |
| **Ensembl Bacteria** | (Varies by strain) | Genome browser and gene annotation. |
| **InterPro** | IPR001279 (Metallo-beta-lactamase) | Protein family classification and domain analysis. |
| **Pfam** | PF00753 (Metallo-beta-lactamase superfamily) | Protein domain family. |
| **Gene Ontology (GO)** | GO:0008800 (beta-lactamase activity); GO:0008270 (zinc ion binding); GO:0046677 (response to antibiotic) | Functional annotation terms. |
| **STRING** | (Varies by organism) | Protein-protein interaction networks (limited interactions). |
| **BioGRID** | (Varies by organism) | Protein interaction data. |
| **CARD (Comprehensive Antibiotic Resistance Database)** | (Varies by variant) | Resistance gene ontology and AMR detection. |
| **ResFinder** | (Varies by variant) | Web-based tool for detecting acquired antimicrobial resistance genes. |

## 8. Mermaid Diagram: Genetic Context and Functional Impact

The following Mermaid diagram illustrates the genetic context of P36503 within a class 1 integron and its functional impact on antibiotic resistance.

```mermaid
flowchart TD
    A["Antibiotic Exposure"] --> B{"DNA Damage"};
    B -->|"SOS Response"| C["LexA Cleavage"];
    C --> D["Integrase Expression"];
    D --> E["Gene Cassette Mobilization"];
    E --> F["P36503 Gene Expression"];
    F --> G["Protein Secretion to Periplasm"];
    G --> H["Zinc Binding & Folding"];
    H --> I["Active Metallo-β-Lactamase"];
    I --> J{"Hydrolysis of β-Lactam Antibiotics"};
    J -->|"Penicillins"| K["Inactive"];
    J -->|"Cephalosporins"| L["Inactive"];
    J -->|"Carbapenems"| M["Inactive"];
    K & L & M --> N["Antibiotic Failure"];
    N --> O["Therapeutic Challenge"];
    O --> P["Need for Alternative Drugs"];
    P --> Q["Colistin, Tigecycline, etc."];
```

## References

The following references provide the foundational literature and data for the information presented in this manual. Due to the specific nature of the gene identifier (P36503), the citations are drawn from the broader literature on metallo-β-lactamases, which is the protein family to which this gene product belongs.

[1] Bush, K., & Jacoby, G. A. (2010). Updated functional classification of β-lactamases. *Antimicrobial Agents and Chemotherapy*, 54(3), 969–976. [https://doi.org/10.1128/AAC.01009-09](https://doi.org/10.1128/AAC.01009-09)

[2] Walsh, T. R., Toleman, M. A., Poirel, L., & Nordmann, P. (2005). Metallo-β-lactamases: the quiet before the storm? *Clinical Microbiology Reviews*, 18(2), 306–325. [https://doi.org/10.1128/CMR.18.2.306-325.2005](https://doi.org/10.1128/CMR.18.2.306-325.2005)

[3] Palzkill, T. (2013). Metallo-β-lactamase structure and function. *Annals of the New York Academy of Sciences*, 1277(1), 91–104. [https://doi.org/10.1111/j.1749-6632.2012.06796.x](https://doi.org/10.1111/j.1749-6632.2012.06796.x)

[4] Cornaglia, G., Giamarellou, H., & Rossolini, G. M. (2011). Metallo-β-lactamases: a last frontier for β-lactams? *The Lancet Infectious Diseases*, 11(5), 381–393. [https://doi.org/10.1016/S1473-3099(11)70056-1](https://doi.org/10.1016/S1473-3099(11)70056-1)

[5] Queenan, A. M., & Bush, K. (2007). Carbapenemases: the versatile β-lactamases. *Clinical Microbiology Reviews*, 20(3), 440–458. [https://doi.org/10.1128/CMR.00001-07](https://doi.org/10.1128/CMR.00001-07)

[6] Bonomo, R. A. (2017). β-Lactamases: A focus on current challenges and future prospects. *Cold Spring Harbor Perspectives in Medicine*, 7(1), a025239. [https://doi.org/10.1101/cshperspect.a025239](https://doi.org/10.1101/cshperspect.a025239)

[7] Gill, M. J., Simjee, S., Alattaq, K., Govan, J. R. W., & Amyes, S. G. B. (1995). The amino acid sequence of a carbapenem-hydrolysing metallo-β-lactamase from *Aeromonas hydrophila*. *Journal of Medical Microbiology*, 42(5), 340–345. [https://doi.org/10.1099/00222615-42-5-340](https://doi.org/10.1099/00222615-42-5-340)

[8] Laraki, N., Franceschini, N., Rossolini, G. M., Santucci, P., Galleni, M., Frère, J. M., & Amicosante, G. (1999). Biochemical characterization of the *Pseudomonas aeruginosa* 101/1477 metallo-β-lactamase IMP-1 produced by *Escherichia coli*. *Antimicrobial Agents and Chemotherapy*, 43(4), 902–906. [https://doi.org/10.1128/AAC.43.4.902](https://doi.org/10.1128/AAC.43.4.902)

[9] Toleman, M. A., Simm, A. M., Murphy, T. A., Gales, A. C., Biedenbach, D. J., Jones, R. N., & Walsh, T. R. (2002). Molecular characterization of SPM-1, a novel metallo-β-lactamase isolated in Latin America: report from the SENTRY antimicrobial surveillance programme. *Journal of Antimicrobial Chemotherapy*, 50(5), 673–679. [https://doi.org/10.1093/jac/dkf210](https://doi.org/10.1093/jac/dkf210)

[10] Poirel, L., Naas, T., & Nordmann, P. (2010). Diversity, epidemiology, and genetics of class D β-lactamases. *Antimicrobial Agents and Chemotherapy*, 54(1), 24–38. [https://doi.org/10.1128/AAC.01512-08](https://doi.org/10.1128/AAC.01512-08)

[11] Nordmann, P., Naas, T., & Poirel, L. (2011). Global spread of carbapenemase-producing Enterobacteriaceae. *Emerging Infectious Diseases*, 17(10), 1791–1798. [https://doi.org/10.3201/eid1710.110655](https://doi.org/10.3201/eid1710.110655)

[12] Partridge, S. R., Kwong, S. M., Firth, N., & Jensen, S. O. (2018). Mobile genetic elements associated with antimicrobial resistance. *Clinical Microbiology Reviews*, 31(4), e00088-17. [https://doi.org/10.1128/CMR.00088-17](https://doi.org/10.1128/CMR.00088-17)

[13] Hall, R. M., & Collis, C. M. (1995). Mobile gene cassettes and integrons: capture and spread of genes by site-specific recombination. *Molecular Microbiology*, 15(4), 593–600. [https://doi.org/10.1111/j.1365-2958.1995.tb02372.x](https://doi.org/10.1111/j.1365-2958.1995.tb02372.x)

[14] Stokes, H. W., & Hall, R. M. (1989). A novel family of potentially mobile DNA elements encoding site-specific gene-integration functions: integrons. *Molecular Microbiology*, 3(12), 1669–1683. [https://doi.org/10.1111/j.1365-2958.1989.tb00153.x](https://doi.org/10.1111/j.1365-2958.1989.tb00153.x)

[15] Drawz, S. M., & Bonomo, R. A. (2010). Three decades of β-lactamase inhibitors. *Clinical Microbiology Reviews*, 23(1), 160–201. [https://doi.org/10.1128/CMR.00037-09](https://doi.org/10.1128/CMR.00037-09)

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