Resistance to antibiotics targeted to the bacterial cell wall

Abstract

Peptidoglycan is the main component of the bacterial cell wall. It is a complex, threedimensional mesh that surrounds the entire cell and is composed of strands of alternating glycan units crosslinked by short peptides. Its biosynthetic machinery has been, for the past five decades, a preferred target for the discovery of antibacterials. Synthesis of the peptidoglycan occurs sequentially within three cellular compartments (cytoplasm, membrane, and periplasm), and inhibitors of proteins that catalyze each stage have been identified, although not all are applicable for clinical use. A number of these antimicrobials, however, have been rendered inactive by resistance mechanisms. The employment of structural biology techniques has been instrumental in the understanding of such processes, as well as the development of strategies to overcome them. This review provides an overview of resistance mechanisms developed toward antibiotics that target bacterial cell wall precursors and its biosynthetic machinery. Strategies toward the development of novel inhibitors that could overcome resistance are also discussed.

Targeting Antibiotic Resistance

“…Its synthesis takes place in three steps, starting in the cytoplasm, passing through the inner‐membrane, and ending in the periplasm (Figure 25). The mechanism of this synthesis has been thoroughly studied and will only be briefly discussed here 122. The initial precursor, UDP‐MurNAc, is generated from UDP‐GlcNAc by the action of the transferase MurA and the reductase MurB.…”

Fosfomycin: Mechanism and Resistance

“…The mechanisms of resistance to fosfomycin have been recently reviewed (Karageorgopoulos et al 2012;Castañeda-García et al 2013;Nikolaidis et al 2014). It should be noted that the breakpoints for fosfomycin susceptibility have been formalized for few species and are different for the Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST).…”

Glycopeptide antibiotics: evolving resistance, pharmacology and adverse event profile

“…Another mechanism involves prevention or destruction of precursors that end in D-Ala by specific dipeptidases and carboxypeptidases [15]. There are seven operons or gene clusters that have been described (vanA, vanB, vanC, vanD, vanE, vanG and vanL) [16]. Among these, vanA and vanB are the most important clinically, especially since they are transferable via transposons.…”