Potent In Vitro and Ex Vivo Anti-Gonococcal Activity of the RpoB Inhibitor Corallopyronin A.
Potent In Vitro and Ex Vivo Anti-Gonococcal Activity of the RpoB Inhibitor Corallopyronin A.
复制标题
作者：
淋病仍然是一个主要的全球公共卫生问题，因为感染发生率很高（2020年估计为8200万例），以及淋病奈瑟菌菌株的出现和传播对以前和目前用于治疗感染的抗生素具有耐药性。鉴于在不久的将来可能进入临床实践的新抗生素的缺乏，人们担心可能会出现无法治疗的淋病病例。为了应对这一危机，世界卫生组织（WHO）与全球抗生素研究与开发伙伴关系（GARDP）合作，寻找和开发新的抗生素。淋病优先理想情况下，这些抗生素还应该对其他性传播生物体具有活性，如沙眼衣原体和/或生殖支原体，它们通常与N。淋病为合并感染。珊瑚焦宁A是一种有效的抗微生物剂，对衣原体具有活性。并通过与RpoB开关区结合来抑制转录。因此，我们测试了珊瑚焦宁A对N.淋病我们还研究了突变频率和对珊瑚焦宁A的潜在耐药模式。我们报道珊瑚焦宁A对敏感和耐药的N.淋球菌菌株，并能根除培养的原代人宫颈上皮细胞的淋球菌感染。关键的是，我们发现自发的耐珊瑚焦宁A的N。当选择4× MIC时，淋病非常罕见（≤10−10）。我们的研究结果支持临床前研究，旨在开发珊瑚焦宁A淋病治疗方案。重要性全球淋病的高发病率，缺乏保护性疫苗，以及N。对目前使用的抗生素表现出抗性的淋病菌株要求开发新的治疗选择。因此，我们研究了珊瑚焦宁A，一种对其他病原体，包括C。沙眼与淋球菌一起经常引起人类的合并感染，可以在体外和离体发挥抗淋球菌作用，并出现潜在的耐药性。我们建议将珊瑚焦宁A视为淋病的潜在未来治疗选择，因为其活性强，耐药性低，以及最近在可规模生产方面的进展。
Gonorrhea remains a major global public health problem because of the high incidence of infection (estimated 82 million cases in 2020) and the emergence and spread of Neisseria gonorrhoeae strains 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 World Health Organization (WHO), in partnership with the Global Antibiotic Research and Development Partnership (GARDP), has made the search for and development of new antibiotics against N. gonorrhoeae a priority. Ideally, these antibiotics should also be 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 is a potent antimicrobial that exhibits activity against Chlamydia spp. and inhibits transcription by binding to the RpoB switch region. Accordingly, we tested the effectiveness of corallopyronin A against N. gonorrhoeae. We also examined the mutation frequency and modes of potential resistance against corallopyronin A. We report that corallopyronin A has potent antimicrobial action against antibiotic-susceptible and antibiotic-resistant N. gonorrhoeae strains and could eradicate gonococcal infection of cultured, primary human cervical epithelial cells. Critically, we found that spontaneous corallopyronin A-resistant mutants of N. gonorrhoeae are exceedingly rare (≤10−10) when selected at 4× the MIC. Our results support pre-clinical studies aimed at developing corallopyronin A for gonorrheal treatment regimens. IMPORTANCE The high global incidence of gonorrhea, the lack of a protective vaccine, and the emergence of N. gonorrhoeae strains expressing resistance to currently used antibiotics demand that new treatment options be developed. Accordingly, we investigated whether corallopyronin A, an antibiotic which is effective against other pathogens, including C. trachomatis, which together with gonococci frequently cause co-infections in humans, could exert anti-gonococcal action in vitro and ex vivo, and potential resistance emergence. We propose that corallopyronin A be considered a potential future treatment option for gonorrhea because of its potent activity, low resistance development, and recent advances in scalable production.
登录
查看更多内容
DOI：
10.1080/14756366.2021.1991336
发表时间：
2022-12
影响因子：
5.6
作者：
Abutaleb NS;Elhassanny AEM;Nocentini A;Hewitt CS;Elkashif A;Cooper BR;Supuran CT;Seleem MN;Flaherty DP
通讯作者：
Flaherty DP
影响因子：
3.2
作者：
Folster, Jason P.;Johnson, Paul J. T.;Shafer, William M.
通讯作者：
Shafer, William M.
影响因子：
3.1
作者：
Ketterer, MR;Shao, JQ;Apicella, MA
通讯作者：
Apicella, MA
影响因子：
4.9
作者：
Golparian, Daniel;Shafer, William M.;Unemo, Magnus
通讯作者：
Unemo, Magnus
影响因子：
5.6
作者：
Jacobsson, Susanne;Golparian, Daniel;Oxelbark, Joakim;Franceschi, Francois;Brown, David;Louie, Arnold;Drusano, George;Unemo, Magnus
通讯作者：
Unemo, Magnus