Journal of Enzyme Inhibition and Medicinal Chemistry (Dec 2022)

Structure-activity relationship studies for inhibitors for vancomycin-resistant Enterococcus and human carbonic anhydrases

  • Weiwei An,
  • Katrina J. Holly,
  • Alessio Nocentini,
  • Ryan D. Imhoff,
  • Chad. S. Hewitt,
  • Nader S. Abutaleb,
  • Xufeng Cao,
  • Mohamed N. Seleem,
  • Claudiu T. Supuran,
  • Daniel P. Flaherty

DOI
https://doi.org/10.1080/14756366.2022.2092729
Journal volume & issue
Vol. 37, no. 1
pp. 1838 – 1844

Abstract

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Vancomycin-resistant enterococci (VRE), consisting of pathogenic Enterococcus faecalis and E. faecium, is a leading cause of hospital-acquired infections (HAIs). We recently repurposed the FDA-approved human carbonic anhydrase (CA) inhibitor acetazolamide (AZM) against VRE agent with the likely mechanism of action for the molecules being inhibition of one, or both, of the bacterial CA isoforms expressed in VRE. To elucidate how inhibitor binding to the enzymes relates to MIC, we further characterised the inhibition constants (Ki) against the E. faecium α-CA (Efα-CA) and γ-CA (Efγ-CA), as well as against human CA I (hCAI) and human CA II (hCAII) to assess selectivity. We have also utilised homology modelling and molecular dynamics (MD) simulations to gain a better understanding of the potential interactions the molecules are making with the targets. In this paper, we elaborate on the SAR for the AZM analogs as it pertains to MIC and Ki for each CA.

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