Resistance: How VanA Strains Get Away With It

The longstanding invincibility of vancomycin (VC) – the last line of antimicrobial therapy for lifethreatening Gram-positive infections – has been compromised over the past decade. The most common and best understood mode of resistance, the VanA type, consists of the replacement of an ester O for an amide NH in the peptide target recognized by the glycopeptide antibiotic. VC targets the C-terminal D-Ala-D-Ala sequence of the peptide portion of Lipid II, an essential intermediate in bacterial cell wall synthesis; binding of VC eventually results in a compromised bacterial cell wall and ultimately cell death. A single heavy atom substitution by VanA resistant bacteria reduces the binding affinity and efficacy of VC by 1000-fold. A lost hydrogen bond and an attendant repulsive lone pair-lone pair interaction, both of which are brought on by the O for NH substitution, are implicated in the VanA resistance mechanism.