Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
Center for Communicable Disease Dynamics, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
J Antimicrob Chemother. 2021 Sep 15;76(10):2569-2577. doi: 10.1093/jac/dkab217.
Novel therapeutic strategies are urgently needed for Neisseria gonorrhoeae, given its increasing antimicrobial resistance. Treatment of oropharyngeal N. gonorrhoeae infections has proven particularly challenging, with most reported treatment failures of the first-line drug ceftriaxone occurring at this site and lower cure rates in recent trials of new antibiotics reported for oropharyngeal infections compared with other sites of infection. However, the accessibility of the oropharynx to topical therapeutics provides an opportunity for intervention. Local delivery of a therapeutic at a high concentration would enable the use of non-traditional antimicrobial candidates, including biological molecules that exploit underlying chemical sensitivities of N. gonorrhoeae but lack the potency or pharmacokinetic profiles required for effective systemic administration.
Two classes of molecules that are thought to limit gonococcal viability in vivo, bile acids and short- and medium-chain fatty acids, were examined for rapid bactericidal activity.
The bile acids deoxycholic acid (DCA) and chenodeoxycholic acid (CDCA), but not other bile acid species, exerted extremely rapid bactericidal properties against N. gonorrhoeae, reducing viability more than 100 000-fold after 1 min. The short-chain fatty acids formic acid and hexanoic acid shared this rapid bactericidal activity. All four molecules are effective against a phylogenetically diverse panel of N. gonorrhoeae strains, including clinical isolates with upregulated efflux pumps and resistance alleles to the most widely used classes of existing antimicrobials. DCA and CDCA are both approved therapeutics for non-infectious indications and are well-tolerated by cultured epithelial cells.
DCA and CDCA are attractive candidates for further development as anti-gonococcal agents.
由于淋病奈瑟菌对抗微生物药物的耐药性不断增加，因此迫切需要新的治疗策略。治疗口咽型淋病奈瑟菌感染极具挑战性，大多数报告的一线药物头孢曲松治疗失败都发生在该部位，而且最近报道的用于口咽感染的新型抗生素试验中，与其他感染部位相比，该部位的治愈率较低。然而，口咽部易于接受局部治疗，为干预提供了机会。局部给予高浓度的治疗药物可使非传统抗菌候选药物得以应用，包括利用淋病奈瑟菌潜在化学敏感性但缺乏有效全身给药所需效力或药代动力学特征的生物分子。
研究了两类被认为会限制体内淋病奈瑟菌生存能力的分子，即胆汁酸和短链及中链脂肪酸，以观察它们是否具有快速杀菌活性。
胆汁酸脱氧胆酸（DCA）和鹅脱氧胆酸（CDCA），但不是其他胆汁酸种类，对淋病奈瑟菌具有极强的快速杀菌特性，在 1 分钟内使活菌减少 100000 倍以上。短链脂肪酸甲酸和己酸也具有这种快速杀菌活性。这四种分子对具有不同进化谱系的淋病奈瑟菌菌株均有效，包括具有上调外排泵和对最广泛使用的现有抗菌药物类别耐药等位基因的临床分离株。DCA 和 CDCA 均为非传染性疾病的批准治疗药物，并且被培养的上皮细胞耐受良好。
DCA 和 CDCA 是作为抗淋病奈瑟菌药物进一步开发的有吸引力的候选药物。
