Version 2 2021-03-26, 13:40Version 2 2021-03-26, 13:40
Version 1 2021-03-25, 21:13Version 1 2021-03-25, 21:13
journal contribution
posted on 2021-03-26, 13:40authored byChad S. Hewitt, Nader S. Abutaleb, Ahmed E. M. Elhassanny, Alessio Nocentini, Xufeng Cao, Devon P. Amos, Molly S. Youse, Katrina J. Holly, Anil Kumar Marapaka, Weiwei An, Jatinder Kaur, Aaron D. Krabill, Ahmed Elkashif, Yehia Elgammal, Amanda L. Graboski, Claudiu T. Supuran, Mohamed N. Seleem, Daniel P. Flaherty
Neisseria gonorrhoeae is an urgent threat to public
health in the United States and around the world. Many of the current
classes of antibiotics to treat N. gonorrhoeae infection
are quickly becoming obsolete due to increased rates of resistance.
Thus, there is a critical need for alternative antimicrobial targets
and new chemical entities. Our team has repurposed the FDA-approved
carbonic anhydrase inhibitor scaffold of acetazolamide to target N. gonorrhoeae and the bacteria’s essential carbonic
anhydrase, NgCA. This study established both structure–activity
and structure–property relationships that contribute to both
antimicrobial activity and NgCA activity. This ultimately led to molecules 20 and 23, which displayed minimum inhibitory
concentration values as low as 0.25 μg/mL equating to an 8-
to 16-fold improvement in antigonococcal activity compared to acetazolamide.
These analogues were determined to be bacteriostatic against the pathogen
and likely on-target against NgCA. Additionally, they did not exhibit
any detrimental effects in cellular toxicity assays against both a
human endocervical (End1/E6E7) cell line or colorectal adenocarcinoma
cell line (Caco-2) at concentrations up to 128 μg/mL. Taken
together, this study presents a class of antigonococcal agents with
the potential to be advanced for further evaluation in N.
gonorrhoeae infection models.