UNDERSTANDING CLASS A BETA-LACTAMASE TOWARDS DRUG RESISTANCE

Abstract

One of the major health-related threats that have been snowballing in the 21st century is the development of anti-microbial resistance (AMR). In 2022, WHO (world health organization) rates AMR as a top 10 global health concern. It usually develops as a result of horizontal gene transfer among compatible groups of bacterial species. There isn’t a single mechanism that is solely responsible for conferring AMR. The most common mechanisms are target-site alteration, alteration of alternative PBPs, altered membrane permeability, metabolic pathway modification, antibiotic degradation, and enzyme-mediated drug inactivation (beta-lactamases). The resistance can be developed intrinsically, acquired, cross-resistance, or multi-drug/pan-drug resistance. If we take beta-lactam drug as an example the resistance to beta-lactam drug is the most threaten because till now it is the most potent antibiotics that our doctors routinely prescribed to us for any bacterial infection. These beta-lactams includes different generation of penicillins, and along with the combination of beta-lactam/beta-lactamase inhibitors, cephalosporins, and last resort carbapenems commonly used against critical infection. Bacteria are now showing resistance against these beta-lactams by conferring a common mechanism of resistance coming from a modifying enzyme called beta-lactamase; it catalyzed hydrolysis of beta-lactam that renders the antibiotics ineffective. Because of the diverse range of substrate specificities of these enzymes, virtually all beta-lactam antibiotics are susceptible to hydrolysis. When these enzymes were studied using structural bioinformatics, it was found that all known three-dimensional structures of beta-lactamase reveals that they are 70-80 percent identical, they have 100 percent structural identity, 100 percent fold and motif identity, and all the enzymes share conserved catalytic serine and other primary catalytic residues (primary active site identity). Besides these structural similarity or conservation, literature studies suggests there are many members of these family that shows diverse catalytic activity, one of the notable example was class A carbapenemase, extended spectrum beta-lactamase (ESBL), and inhibitor resistance beta-lactamase (IRT). Even in a single organism various diverse enzymes are found to perform the same function creating the pathogen most resistance to the last resort of the beta-lactam drugs even the beta-lactamase inhibitor drugs. Together all this the vast diversity among beta-lactamase and their catalytic diversity creates a problem for the evaluation of new antibiotic. To address this issue one of the rational strategy would be characterization of different beta-lactamase to understand the basis of this catalytic divergence.