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

Abstract

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 (K_i) 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 K_i for each CA.

Keywords:

• Carbonic anhydrase inhibitors
• vancomycin-resistant Enterococcus
• antibiotics
• drug repurposing

Author contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

Disclosure statement

Dr. CT Supuran is Editor-in-Chief and Dr. Flaherty is on the Editorial Board of the Journal of Enzyme Inhibition and Medicinal Chemistry. Neither author was involved in the assessment, peer review, or decision-making process of this paper. The authors have no relevant affiliations of financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No potential conflict of interest was reported by the author(s).

Additional information

Funding

The research program was partially funded by a Purdue Institute for Drug Discovery Programmatic [Grant (M.N.S and D.P.F.) and NIH/NIAID 1R01AI148523 (M.N.S and D.P.F.)]. This work was also supported by the Italian Ministry for University and Research, [grant FISR2019_04819 BacCAD (C.T.S.)].