Mechanistic Studies Of Antibiotic Resistance: Developing Novel Approaches To Overcome Kpc Β-Lactamases; A Global Threat

Abstract

One of the most common mechanisms of β-lactam antibiotic resistance that has been clinically observed is the expression of β-lactamases. β-lactamases are enzymes that have the ability to degrade the β-lactam antibiotic. The numbers of these β-lactamases are growing, reaching increased threat levels. Thus, there is an urgent need to develop potent β-lactamases inhibitors. Klebsiella pneumoniae carbapenemase 2 (KPC-2) is a class A serine β-lactamase possess a significant clinical threat as this -lactamase primarily confers resistance to many β-lactam antibiotics, including penicillins, carbapenems and cephalosporins and is not readily inhibited by the β-lactamase inhibitors clavulanic acid, sulbactam and tazobactam. My dissertation work focuses on understanding the mechanism of resistance for two KPC-2 variants (D179N and D179Y KPC-2) to β-lactam/β-lactamase inhibitor combination (ceftazidime/avibactam) which could lead to the design of improved inhibitors. Also, we used other β-lactamases inhibitors such as vaborbactam and relebactam with these KPC-2 variants and compared them with avibactam. Finally, we screened boronic acid compounds to identify and characterize novel inhibitors for KPC-2.