Flashtalk 25th International Pathogenic Neisseria Conference 2026

A small molecule and its derivatives inhibit Neisseria gonorrhoeae Type IV pilus expression and Gc survival (#075)

Kathleen R. Nicholson 1 , Shaohui Yin 1 , Nouri Neamati 2 , Jennifer L. Edwards 3 , Chi-Hao Luan 4 , Hank Seifert 1
  1. Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
  2. Department of Medicinal Chemistry, College of Pharmacy, Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
  3. Center for Microbial Pathogenesis, Abigail Wexner Research Institute at Nationwide Children's Hospital, The Ohio State University, Columbus, OH, USA
  4. High Throughput Analysis Laboratory and Department of Molecular Biosciences, Northwestern University, Evanston, IL, USA

Neisseria gonorrhoeae is becoming increasingly resistant to antimicrobials. N. gonorrhoeae requires the Type IV pilus (T4p) for pathogenesis, where the T4p promotes colonization through adherence to host cells and resists neutrophil killing. The pilus also facilitates natural transformation and twitching motility. Collectively, these critical functions make the T4p an attractive drug target. Previously, we developed a high-throughput screen to identify compounds with activity against the zinc metalloprotease Mpg, which is involved in T4p biogenesis. Here, we identified a small-molecule lead compound that inhibits the peptidoglycan-hydrolyzing activity of Mpg, and treatment with 1 μM leads to a decrease in the number of T4p. This small molecule exhibits an additional bacteriostatic effect on N. gonorrhoeae and other bacterial species at doses above 1 μM, independent of Mpg. Importantly, this lead compound inhibits N. gonorrhoeae colonization and prevents survival within two cell culture models of infection at 1 μM without toxic effects on host cells. We have also identified related compounds that also inhibit growth of N. gonorrhoeae. This work provides the initial characterization of a novel class of molecules with antimicrobial and antivirulence activity against N. gonorrhoeae and other bacterial species.