Gonorrhea is a sexually transmitted disease caused by the bacterial pathogen Neisseria gonorrhoeae
that colonizes urogenital, anal, and nasopharyngeal tissues. Locally in the United States the Centers for Disease
Control and Prevention (CDC) reported a 67% increase of gonorrhea cases between 2013 – 2017 with >550,000
cases in 2017 alone. N. gonorrhoeae wreaks havoc on world health care systems causing pelvic inflammatory
disease, infertility and ectopic pregnancies. The bacteria can also be transmitted from mother to child during
birth and lead to blindness. If left untreated N. gonorrhoeae can cause gonococcemia resulting in skin infection,
arthritis or endocarditis. Pathogenic gonorrhea strains are increasingly resistant to common front-line antibiotics.
The WHO surveillance program reports resistance to most available antibiotics. Rampant resistance has caused
the CDC and the World Health Organization each to classify N. gonorrhoeae as a superbug and a future with an
untreatable gonococcal infection is a real possibility. Thus, there is significant unmet need to identify novel targets
and molecules with therapeutic potential. Studies proposed in this application build upon discoveries that FDA-
approved carbonic anhydrase inhibitors (CAIs), such as acetazolamide and ethoxzolamide, display potent
antimicrobial activity, in an applicable clinical range, against N. gonorrhoeae. CAIs, and analogs we have
designed, also have no antimicrobial effect on commensal bacteria reducing the potential for problematic
dysbiosis caused by antibiotic treatment. We have shown that the molecules exhibit their antibiotic effect by
inhibiting the carbonic anhydrase from N. gonorrhoeae and have validated N. gonorrhoeae carbonic anhydrase
(NgCA) as a viable anti-gonococcal therapeutic target. Our team has improved the potency of the CAI-based
inhibitors from 4 µg/mL to 0.5 µg/mL. This proposal will continue lead optimization of CAI-based analogs using
structure-based design while incorporating modifications to improve permeability into the Gram-negative cell.
Molecules will be assessed in in vitro antimicrobial assays and prioritized analogs will progress to in vitro
pharmacokinetic (PK) and pharmacologic profiling. Finally, top performing analogs will be assessed for in vivo
efficacy in various gonorrhea mouse models as well evaluated the in safety and pharmacokinetic assay to
support future lead selection and investigational new drug enabling studies.