Classification of β-Lactamases: Classes A, B, C, and D

Antibiotic resistance presents a significant challenge to modern medicine. Among the various mechanisms bacteria employ to evade antibiotic action, the production of β-lactamases is particularly concerning. These enzymes degrade β-lactam antibiotics, rendering them ineffective and complicating treatment strategies.

β-Lactamases are categorized into four primary classes: A, B, C, and D. Each class exhibits distinct structural features and mechanisms of action, contributing differently to bacterial resistance profiles.

Class A Enzymes

Class A β-lactamases are among the most studied due to their widespread presence in various bacterial species. These enzymes are known for their ability to hydrolyze a broad spectrum of β-lactam antibiotics, including penicillins and cephalosporins. Structurally, Class A enzymes possess a serine residue at their active site, which plays a pivotal role in the acylation and deacylation processes during antibiotic degradation. This serine-based mechanism is a defining characteristic that distinguishes them from other classes.

The genetic basis for Class A β-lactamases is often found on plasmids, which facilitates their horizontal transfer between bacteria. This mobility contributes to the rapid dissemination of resistance traits across different bacterial populations. Notable examples of Class A enzymes include TEM-1, SHV-1, and the more recently identified CTX-M variants. Each of these enzymes has evolved to target specific antibiotics, with CTX-M enzymes showing a particular affinity for cefotaxime, a third-generation cephalosporin.

In recent years, the emergence of extended-spectrum β-lactamases (ESBLs) within Class A has raised significant concerns. These ESBLs have expanded their substrate range to include even more advanced cephalosporins, posing challenges for clinical treatment. The development of inhibitors such as clavulanic acid has been a strategic response to counteract these enzymes. By binding to the active site, these inhibitors prevent the enzyme from interacting with the antibiotic, thereby preserving the drug’s efficacy.

Class B Enzymes

Diverging from other β-lactamase classes, Class B enzymes, also known as metallo-β-lactamases (MBLs), possess a unique mechanism that relies on zinc ions for their catalytic activity. This metal ion dependency sets them apart, offering a distinct method for breaking down antibiotics. Unlike their serine-based counterparts, these enzymes use zinc to coordinate the hydrolysis of the β-lactam ring, which allows them to target a diverse array of antibiotics, including carbapenems, often reserved for severe infections.

Their reliance on metal ions presents both challenges and opportunities in developing inhibitors. While traditional β-lactamase inhibitors fail to affect these enzymes, researchers are exploring metal chelating agents as potential inhibitors. These agents aim to sequester the zinc ions, thereby hindering the enzyme’s activity. The discovery of MBL inhibitors is an active area of research, with compounds like aspergillomarasmine A showing promise in preclinical studies.

The genetic diversity of Class B enzymes is noteworthy, with the IMP, VIM, and NDM families being prominent examples. The NDM enzymes, in particular, have garnered attention due to their rapid global spread and association with multidrug-resistant bacterial strains. These enzymes are often encoded on mobile genetic elements, facilitating their transmission across different bacterial species and complicating efforts to control resistance.

Class C Enzymes

Distinct from other categories, Class C β-lactamases are often referred to as AmpC enzymes. These enzymes are predominantly chromosomally encoded, although plasmid-mediated variants have been identified, contributing to their spread. AmpC enzymes are primarily associated with resistance to cephalosporins and are often found in organisms like Enterobacter, Citrobacter, and Pseudomonas. These bacteria can produce AmpC enzymes constitutively or induce their expression in response to exposure to β-lactam antibiotics, adding a layer of complexity to treatment strategies.

The inducible nature of AmpC enzymes is particularly problematic in clinical settings. When exposed to certain antibiotics, these bacteria can upregulate enzyme production, leading to treatment failure. This inducibility is often mediated by regulatory genes that respond to the presence of antibiotics, making it challenging to predict resistance patterns. As such, the presence of AmpC enzymes necessitates careful antibiotic selection and dosing strategies to avoid inadvertently triggering resistance.

Efforts to combat AmpC-mediated resistance include the use of non-β-lactam antibiotics or combination therapies that pair β-lactams with inhibitors targeting other resistance mechanisms. While traditional β-lactamase inhibitors are ineffective against AmpC enzymes, ongoing research aims to develop novel compounds that can effectively target these resistant strains.

Class D Enzymes

Class D β-lactamases, often referred to as OXA-type enzymes, present a diverse and evolving challenge in the landscape of antibiotic resistance. These enzymes are particularly notorious for their ability to hydrolyze oxacillin and related penicillins, with certain variants also targeting carbapenems, which are typically reserved for serious infections. The structural diversity within Class D enzymes is significant, with over 200 variants identified, each exhibiting unique substrate profiles and resistance mechanisms.

This class is frequently associated with Acinetobacter species, notorious for causing hospital-acquired infections. The adaptability of Class D enzymes is evident in their ability to evolve rapidly, allowing them to broaden their activity spectrum and evade newly developed antibiotics. This adaptability is partly due to the genetic plasticity of the bacteria that harbor these enzymes, which can acquire and disseminate resistance genes through horizontal gene transfer.