Potential Drug Candidate for Inhibiting β -Lactamase Enzymes of Class A and Carbapenemase

Abstract β -lactamases enzymes ( β -LEs) are used to neutralize β -lactam (BLM) antibiotics by rendering them inactive. Over time, these enzymes evolve to expand their range of activity, particularly in class A β -lactamases (BLs), leading to significant clinical concerns. As carbapenems are the most effective antibiotics, resistance against them is of major concern. Further, mechanism-based β -lactamase (BL) inhibitors were introduced against β -LEs of class A to break the chain of resistance. However, some of the enzymes of this class have clinically mutated to such an extent that many currently available β -lactamase inhibitors have also become ineffective. Hence, there is a serious need to propose an effective drug candidate against such resistant β -LEs producing bacterial infections because otherwise, it would be very difficult and complex to treat them. Molecular docking, ADMET analysis, molecular dynamics simulation, MM/GBSA, and PCA were done to propose an effective novel drug candidate against β -LEs of class A and SME1 carbapenemase. This drug has a structural analogy to the available antibiotic and shows a good binding affinity and stability with an expanded spectrum of β -LEs like TEM52 and Mycobacterium tuberculosis BlaC, as well as carbapenemase SME1. This drug attempts to tackle a significant problem in clinical settings, the increase in resistance to carbapenems and BLM antibiotics brought on by clinically altered class A β -LEs, especially carbapenemases like SME1. It acts specifically on BL-producing bacteria, which degrade the BL ring of penicillins, cephalosporins, and other antibiotics and thus inactivate them. This drug acts by inhibiting these enzymes to protect BLM antibiotics from degradation, increasing their activity spectrum. Hence, this drug is proposed to be an effective medicine in combating antibiotic-resistant organisms. Graphic abstract