Inhibiting antimicrobial drug resistance
Molecular basis for the potent inhibition of the emerging carbapenemase VCC-1 by avibactam. Mangat CS*, Vadlamani G, Holicek V, Chu M, Larmour VLC, Vocadlo DJ, Mulvey MR*, Mark BL. Antimicrob Agents Chemother 2019 Mar 27; 63(4).e02112-18. doi: https://doi.org/10.1128/AAC.02112-18
The research examined in this science story, in combination with laboratory-based surveillance, is an example of the wide scope of activities conducted in the fight against antimicrobial resistance (AMR). This collaborative work directed at developing a better understanding of resistance mechanisms is important evidence to help address this priority public health issue.
What was known about this area prior to your work, and why was the research done?
AMR in bacteria is a serious threat to global public health as it limits antibiotic treatment options. In Canada, trends in AMR and antimicrobial use along the farm-to-fork continuum are monitored by the Canadian Integrated Program for Antimicrobial Resistance Surveillance (CIPARS). This program’s work is important as it provides scientific evidence to help inform infection prevention and control efforts among animals, food and people. When examining imported retail seafood as part of a special surveillance project, a Vibrio cholerae isolate was found with a novel gene making the organism resistant to carbapenems. Carbapenems are a class of antibiotic drugs that historically have low rates of resistance, and often used as last-line treatment options. The drug resistance is due to a novel enzyme called VCC-1 (Vibrio cholera carbapenemase-1). Carbapenemase enzymes inactivate carbapenem drugs and make them ineffective. This study aims to understand the relationship between VCC-1 and avibactam, a substance known to interrupt the activity of some enzymes responsible for AMR.
What are your most significant findings from this work?
This research found that avibactam inhibits the VCC-1 enzyme by trapping it and making the bacteria sensitive to antimicrobial carbapenem drugs. Avibactam can be used in combination with antimicrobial drugs to treat complicated infections. However, some carbapenemase enzymes, such as Klebsiella pneumoniae carbapenemase (KPC), tightly bind and slowly degrade avibactam making its benefit short-lived. This was not the case with the VCC-1 enzyme, which only fleetingly binds avibactam, which led the researchers to study its 3D structure and binding of avibactam. Understanding how these two items interact may help explain why VCC-1 does not break down avibactam. The VCC-1 and KPC enzymes were also compared and a small structural difference was found, which could explain the short-lived interaction between avibactam and VCC-1. While the mechanism breaking down avibactam is still unknown, the noted structural difference may explain why KPC releases avibactam more slowly than VCC-1. This difference in contact time may contribute how avibactam is degraded. Further research on this hypothesis may help uncover how avibactam remains intact and active or is eventually degraded.
What are the implications or impact of the research?
The research has shown that avibactam is effective against organisms with the VCC-1 enzyme. To date, VCC-1 has been found in limited aquaculture or seafood sources. However, if the VCC-1 gene is transferred to other disease-causing bacteria, avibactam’s effectiveness in neutralizing drug resistance would be critical for treatment. This type of AMR sharing occurs frequently in bacteria. It should also be noted that avibactam’s effectiveness against some AMR enzymes (e.g. KPC) may lessen as those bacteria evolve in response to antibiotic drug overuse or misuse. Public health tools such as whole genome sequencing and active AMR surveillance help researchers better understand AMR and factors like the mechanisms behind avibactam degradation.
Additional References of Significance:
- Janecko N, Martz S-L*, Avery BP*, Daignault D*, Desruisseau A*, Boyd D*, Irwin RJ, Mulvey MR*, Reid-Smith RJ. Carbapenem-resistant Enterobacter spp. in retail seafood imported from Southeast Asia to Canada. Emerg Infect Dis 2016 Sep; 22(9):1675-7. doi: https://doi.org/10.3201/eid2209.160305
- Mangat CS*, Boyd D*, Janecko N, Martz S-L, Desruisseau A*, Carpenter M*, Reid-Smith RJ, Mulvey MR*. Characterization of VCC-1, a novel Ambler class A carbapenemase from Vibrio cholerae isolated from imported retail shrimp sold in Canada. Antimicrob Agents Chemother 2016 Jan 11; 60(3):1819-25. doi: https://dx.doi.org/10.1128/AAC.02812-15
- Ehmann DE, Jahić H, Ross PL, Gu R-F, Hu J, Kern G, Walkup GK, Fisher SL. Avibactam is a covalent, reversible, non-β-lactam β-lactamase inhibitor. Proc Natl Acad Sci U S A. 2012 Jul 17; 109(29):11663-8. doi: https://doi.org/10.1073/pnas.1205073109
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