Inhibition of pathogenic bacterial carbonic anhydrases by monothiocarbamates

Abstract

Carbonic anhydrases (CAs) from the pathogenic bacteria Nesseria gonorrhoeae and vancomycin-resistant enterococci (VRE) have recently been validated as antibacterial drug targets. Here we explored the inhibition of the α-CA from N. gonorrhoeae (α-NgCA), of α- and γ-class enzymes from Enterococcus faecium (α-EfCA and γ-EfCA) with a panel of aliphatic, heterocyclic and aryl-alkyl primary/secondary monothiocarbamates (MTCs). α-NgCA was inhibited in vitro with K_Is ranging from 0.367 to 0.919 µM. The compounds inhibited the α-EfCA and γ-EfCA with K_I ranges of 0.195–0.959 µM and of 0.149–1.90 µM, respectively. Some MTCs were also investigated for their inhibitory effects on the growth of clinically-relevant N. gonorrhoeae and VRE strains. No inhibitory effects on the growth of VRE were noted for all MTCs, whereas one compound (13) inhibited the growth N. gonorrhoeae strains at concentrations ranging from 16 to 64 µg/mL. This suggests that compound 13 may be a potential antibacterial agent against N. gonorrhoeae.

Keywords:

• Antibacterials
• carbonic anhydrase inhibitor
• monothiocarbamates
• Neisseria gonorrhoeae
• vancomycin-resistant enterococci

Disclosure statement

CT Supuran is Editor-in-Chief of the Journal of Enzyme Inhibition and Medicinal Chemistry. He was not 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.

Additional information

Funding

C.T.S. thanks the Italian Ministry for University and Research (MIUR), project [FISR2019_04819 BacCAD] and EU – Horizon2020, for the project Springboard grant agreement [No. 951883]. The research program was also partially funded by NIH/NIAID [1R01AI148523] (to M.N.S. and D.P.F.) as well as NIH/NIAID 1R01AI153264 (to. D.P.F. and M.N.S.).