ERP138131 PRJEB53342 3ed3be66-ce19-45d7-b65f-3eefb054b278 Potent in-vitro and ex-vivo anti-gonococcal activity of the RpoB inhibitor Corallopyronin A Gonorrhea remains a major global public health problem because of the high incidence of infection (estimated 82 million cases in 2020) as well as the emergence and spread of Neisseria gonorrhoeae strains that are resistant to previous and current antibiotics used to treat infections. Given the dearth of new antibiotics that are likely to enter clinical practice in the near future, there is concern that cases of untreatable gonorrhea might emerge. In response to this crisis, the WHO, in partnership with GARDP, has made the search for, and development of, new antibiotics against N. gonorrhoeae a priority. Ideally, these antibiotics are additionally active against other sexually transmitted organisms, such as Chlamydia trachomatis and/or Mycoplasma genitalium, which are often found with N. gonorrhoeae as co-infections. Corallopyronin A (CorA) is a potent antimicrobial that inhibits bacterial transcription by binding to the switch region of RpoB. Accordingly, we tested the effectiveness of CorA against N. gonorrhoeae. We also examined the mutation frequency and mode of potential resistance against CorA. We report that it has potent antimicrobial action against antibiotic-susceptible and -resistant N. gonorrhoeae strains and could eradicate gonococcal infection of cultured human cervical epithelial cells. Critically, we found that spontaneous CorA-resistant mutants of N. gonorrhoeae are exceedingly rare (=10-10). Collectively, our results support continuation of pre-clinical studies aimed at developing CorA for future gonorrheal treatment regimens. Gonorrhea remains a major global public health problem because of the high incidence of infection (estimated 82 million cases in 2020) as well as the emergence and spread of Neisseria gonorrhoeae strains that are resistant to previous and current antibiotics used to treat infections. Given the dearth of new antibiotics that are likely to enter clinical practice in the near future, there is concern that cases of untreatable gonorrhea might emerge. In response to this crisis, the WHO, in partnership with GARDP, has made the search for, and development of, new antibiotics against N. gonorrhoeae a priority. Ideally, these antibiotics are additionally active against other sexually transmitted organisms, such as Chlamydia trachomatis and/or Mycoplasma genitalium, which are often found with N. gonorrhoeae as co-infections. Corallopyronin A (CorA) is a potent antimicrobial that inhibits bacterial transcription by binding to the switch region of RpoB. Accordingly, we tested the effectiveness of CorA against N. gonorrhoeae. We also examined the mutation frequency and mode of potential resistance against CorA. We report that it has potent antimicrobial action against antibiotic-susceptible and -resistant N. gonorrhoeae strains and could eradicate gonococcal infection of cultured human cervical epithelial cells. Critically, we found that spontaneous CorA-resistant mutants of N. gonorrhoeae are exceedingly rare (=10-10). Collectively, our results support continuation of pre-clinical studies aimed at developing CorA for future gonorrheal treatment regimens. ENA-FIRST-PUBLIC 2022-09-13 ENA-LAST-UPDATE 2022-09-13