β-lactam resistance: The role of low molecular weight penicillin binding proteins, β-lactamases and ld-transpeptidases in bacteria associated with respiratory tract infections.

Abstract

Disruption of peptidoglycan (PG) biosynthesis in the bacterial cell wall by β-lactam antibiotics has transformed therapeutic options for bacterial infections. These antibiotics target the transpeptidase domains in penicillin binding proteins (PBPs), which can be classified into high and low molecular weight (LMW) counterparts. While the essentiality of the former has been extensively demonstrated, the physiological roles of LMW PBPs remain poorly understood. Herein, we review the function of LMW PBPs, β-lactamases and ld-transpeptidases (Ldts) in pathogens associated with respiratory tract infections. More specifically, we explore their roles in mediating β-lactam resistance. Using a comparative genomics approach, we identified a high degree of genetic redundancy for LMW PBPs which retain the motifs, SxxN, SxN and KTG required for catalytic activity. Differences in domain architecture suggest distinct physiological roles, possibly related to bacterial cell cycle and/or adaptation to various environmental conditions. Many of the LMW PBPs play an important role in β-lactam resistance either through mutation or variation in abundance. In all of the bacterial genomes assessed, at least one β-lactamase homologue is present, suggesting that enzymatic degradation of β-lactams is a highly conserved resistance mechanism. Furthermore, the presence of Ldt homologues in the majority of species surveyed suggests that alternative PG crosslinking may further mediate β-lactam drug resistance. A deeper understanding of the interplay between these different mechanisms of β-lactam resistance will provide a framework for new therapeutics, which are urgently required given the rapid emergence of antimicrobial resistance. © 2018 IUBMB Life, 70(9):855-868, 2018.