Molecular Basis for the Potent Inhibition of the Emerging Carbapenemase VCC-1 by Avibactam

Antimicrob Agents Chemother. 2019 Mar 27;63(4):e02112-18. doi: 10.1128/AAC.02112-18. Print 2019 Apr.

Abstract

In 2016, we identified a new class A carbapenemase, VCC-1, in a nontoxigenic Vibrio cholerae strain that had been isolated from retail shrimp imported into Canada for human consumption. Shortly thereafter, seven additional VCC-1-producing V. cholerae isolates were recovered along the German coastline. These isolates appear to have acquired the VCC-1 gene (blaVCC-1) independently from the Canadian isolate, suggesting that blaVCC-1 is mobile and widely distributed. VCC-1 hydrolyzes penicillins, cephalothin, aztreonam, and carbapenems and, like the broadly disseminated class A carbapenemase KPC-2, is only weakly inhibited by clavulanic acid or tazobactam. Although VCC-1 has yet to be observed in the clinic, its encroachment into aquaculture and other areas with human activity suggests that the enzyme may be emerging as a public health threat. To preemptively address this threat, we examined the structural and functional biology of VCC-1 against the FDA-approved non-β-lactam-based inhibitor avibactam. We found that avibactam restored the in vitro sensitivity of V. cholerae to meropenem, imipenem, and ertapenem. The acylation efficiency was lower for VCC-1 than for KPC-2 and akin to that of Pseudomonas aeruginosa PAO1 AmpC (k2/Ki = 3.0 × 103 M-1 s-1). The tertiary structure of VCC-1 is similar to that of KPC-2, and they bind avibactam similarly; however, our analyses suggest that VCC-1 may be unable to degrade avibactam, as has been found for KPC-2. Based on our prior genomics-based surveillance, we were able to target VCC-1 for detailed molecular studies to gain early insights that could be used to combat this carbapenemase in the future.

Keywords: VCC-1; Vibrio cholerae; X-ray structure; avibactam; carbapenemase; carbapenems; β-lactamases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Azabicyclo Compounds / pharmacology*
  • Aztreonam / metabolism
  • Bacterial Proteins / antagonists & inhibitors*
  • Carbapenems / metabolism
  • Carbapenems / pharmacology*
  • Cephalothin / metabolism
  • Humans
  • Microbial Sensitivity Tests
  • Penicillins / metabolism
  • Seafood / microbiology
  • Vibrio cholerae / drug effects*
  • Vibrio cholerae / genetics
  • Vibrio cholerae / isolation & purification
  • beta-Lactamase Inhibitors / pharmacology*
  • beta-Lactamases

Substances

  • Azabicyclo Compounds
  • Bacterial Proteins
  • Carbapenems
  • Penicillins
  • beta-Lactamase Inhibitors
  • avibactam
  • VCC-1 protein, Vibrio cholerae
  • beta-Lactamases
  • carbapenemase
  • Aztreonam
  • Cephalothin