Scientists in Canada say they have found a method to block the VCC-1 enzyme, which disables the VCC-1 antimicrobial-resistance gene. VCC-1, a ß-lactamase gene, has been discovered in benign close relatives of virulent Vibrio cholerae, which causes cholera.
The study (“Molecular basis for the potent inhibition of the emerging carbapenemase VCC-1 by avibactam”) appears online in Antimicrobial Agents and Chemotherapy.
“In 2016 we identified a new class A carbapenemase, VCC-1, in nontoxigenic Vibrio cholerae that had been isolated from retail shrimp imported into Canada for human consumption. Shortly thereafter, seven additional VCC-1 producing V. cholerae were isolated along the German coastline. These isolates appear to have acquired the VCC-1 gene (blaVCC-1) independently from the Canadian isolate, suggesting 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 the enzyme may be emerging as a public health threat,” wrote the investigators.
“To pre-emptively 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, impenem, and ertapenem. Acylation efficiency was lower for VCC-1 as compared to KPC-2 and akin to that of Pseudomonas aeruginosa PAO1 AmpC (k2/Ki=3.0 × 103 M-1sec-137). 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.”
“We noticed that VCC-1 belongs to the same class of [antibiotic resistance] enzymes that avibactam is active against,” said lead author Brian Mark, PhD, professor, department of microbiology, University of Manitoba. The FDA had recently approved avibactam. “I said, ‘lets try avibactam,’ and sure enough, it blocks the enzyme quite potently,” said Mark.
To see how avibactam did so, he and his collaborators used x-ray crystallography, which showed that the avibactam molecule has a protuberance that fits snugly into a pocket on VCC-1, “the same pocket that VCC-1 uses to break down the antibiotic,” said Mark.
After that, “we went back to the original strain, the Vibrio the VCC-1 was originally found in,” continued Mark. “We grew it up, and demonstrated that if you try to kill this bacteria with carbapenem [an important beta lactam antimicrobial], it is very resistant, which is alarming, as this is a front line, last resort antibiotic, and here it is sitting on shrimp that people are eating. But if you add avibactam to the carbapenem, it becomes really potent, because you blocked the VCC-1 which was enabling the resistance.”
The FDA recently approved a combination drug containing avibactam and the antibiotic, ceftazidime. Should a patient enter a clinic ill with a pathogen carrying VCC-1, knowledgeable physicians will be ready, added Mark.