Identification of new antimicrobial agents to combat antibiotic resistance

Abstract

One of the utmost relevant categories of antibiotics used to cure the clinical bacterial diseases are beta lactam drugs. But the routine and irregular application of this class of antibiotic causes emergence and expanding spread of resistance mechanisms, especially that interceded by beta lactamases. Beta lactamases have ability to degrade almost all classes of beta lactam drugs. beta lactamases of different classes exhibit ample sequence and structural diversity also distinct, although imbricate substrate spectrum. Gram negative microorganisms with multi drug resistance and ever-increasing substrate specificity dispersing rapidly across the world represents an alarming stage of fight against antibiotic resistance. The limited options of antibiotics compel researchers to identify novel methods to fight against antibiotic resistance. One of the novel approaches is the application of an inhibitor molecule in combination with antibiotic, so that inhibitor can block the enzymatic activity of beta lactamases while antibiotic can carry out its bactericidal effect at the same time. newlineIn view of this, present study was caried out to identify novel non beta lactam beta lactamases inhibitors possessing broad spectrum inhibitory activity against prevalent beta lactamases. A combination of in-silico as well as in vitro techniques were employed for the investigation. newlineThis study successfully identified three potential inhibitors having ability to block SHV 1, TEM 1, KPC 2, CTXM 15, NDM 1, Amp C and OXA 48 and two novel non beta lactam inhibitors competent to inhibit selected OXA variants. The chapter four involves the structure-based screening of non beta lactam inhibitors against class D beta lactamases and concluded with the identification of two novel non beta-lactam inhibitors that complement the active site of selected OXA variants and interact with conserved residues involved in beta lactam recognition and hydrolysis. These identified beta lactamase inhibitors are competent for MBLs and SBLs simultaneously. newline newline newline