Molecular mechanisms of vancomycin resistance

Abstract

Vancomycin and related glycopeptides are drugs of last resort for the treatment of severe infections caused by Gram‐positive bacteria such as Enterococcus species, Staphylococcus aureus, and Clostridium difficile. Vancomycin was long considered immune to resistance due to its bactericidal activity based on binding to the bacterial cell envelope rather than to a protein target as is the case for most antibiotics. However, two types of complex resistance mechanisms, each comprised of a multi‐enzyme pathway, emerged and are now widely disseminated in pathogenic species, thus threatening the clinical efficiency of vancomycin. Vancomycin forms an intricate network of hydrogen bonds with the d‐Ala‐d‐Ala region of Lipid II, interfering with the peptidoglycan layer maturation process. Resistance to vancomycin involves degradation of this natural precursor and its replacement with d‐Ala‐d‐lac or d‐Ala‐d‐Ser alternatives to which vancomycin has low affinity. Through extensive research over 30 years after the initial discovery of vancomycin resistance, remarkable progress has been made in molecular understanding of the enzymatic cascades responsible. Progress has been driven by structural studies of the key components of the resistance mechanisms which provided important molecular understanding such as, for example, the ability of this cascade to discriminate between vancomycin sensitive and resistant peptidoglycan precursors. Important structural insights have been also made into the molecular evolution of vancomycin resistance enzymes. Altogether this molecular data can accelerate inhibitor discovery and optimization efforts to reverse vancomycin resistance. Here, we overview our current understanding of this complex resistance mechanism with a focus on the structural and molecular aspects.

New Antimicrobial Bioactivity against Multidrug-Resistant Gram-Positive Bacteria of Kinase Inhibitor IMD0354

“…Vancomycin is a glycopeptide able to inhibit cell wall synthesis by binding to the ends of D-Ala-D-Ala moieties of un-crosslinked Lipid II molecules [ 4 ]. Vancomycin is an antibiotic effective at treating Gram-positive multidrug-resistant pathogens, including MRSA [ 4 , 5 ].…”

“…Vancomycin is a glycopeptide able to inhibit cell wall synthesis by binding to the ends of D-Ala-D-Ala moieties of un-crosslinked Lipid II molecules [ 4 ]. Vancomycin is an antibiotic effective at treating Gram-positive multidrug-resistant pathogens, including MRSA [ 4 , 5 ]. However, strains such as vancomycin-intermediate Staphylococcus aureus (VISA, minimal inhibitory concentration (MIC) = 4–8 µg/mL), vancomycin-resistant Staphylococcus aureus (VRSA, MIC ≥ 16 µg/mL), as well as vancomycin-resistant enterococci (VRE) have emerged [ 5 , 6 , 7 , 8 , 9 ].…”

“…Vancomycin is able to bind them and thus block PBPs’ attachment and crosslinking. This eventually leads to osmatic stress and bursting of the cell wall making vancomycin a potent bactericidal antibiotic [ 4 ].…”

“…Initially, it had been thought that resistance to vancomycin would be minimal given that it does not target enzymatic cell processes [ 4 ]. However, we now understand that vancomycin resistance is achieved by a group of genes encoding various enzymes and regulatory proteins that alter the original structure of Gram-positive bacterial walls [ 4 , 10 , 11 ]. These groups of genes are usually referred to as resistance cassettes.…”

“…For vancomycin, the originally discovered cassette was named the “VanA”-type cassette which is composed of vanHAX cluster encoding enzymes and vanR and vanS genes that work as a two-component regulation system [ 12 ]. Numerous other resistance cassettes to vancomycin have been discovered and described, each of which includes VanA homologs [ 4 ]. These resistance cassettes encode genes that facilitate the conversion of D-Ala to D-Lac.…”