L S A Rosa Thabatta, Marques Maria Angela M, Yuan Tianao, Bertoluci Daniele F F, Werman Joshua, da M R Costa Fabricio, Fischbacher Linda A, Hacker Mariana de Andrea, Lahiri Ramanuj, Bêrredo-Pinho Márcia, Rosa Patrícia S, Belisle John T, Sampson Nicole S, V Pessolani Maria Cristina
Laboratório de Microbiologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, State of Rio de Janeiro, Brazil.
Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, USA.
Microbiol Spectr. 2025 Jul;13(7):e0022825. doi: 10.1128/spectrum.00228-25. Epub 2025 May 27.
Although the current multidrug therapy (MDT) for leprosy is very successful, the long treatment duration and the emergence of antibiotic-resistant strains demand for new alternative drugs. One potential target for drug development against pathogenic mycobacteria is their need to degrade host cholesterol during infection. , due to its degenerate genome, has preserved only the first step of cholesterol catabolism, in which cholesterol is oxidized to cholestenone by the enzyme 3β-hydroxysteroid dehydrogenase (3β-HSD). avidly produces cholestenone and this metabolic activity seems to play an important role in bacterial pathogenesis. In this study, six 6-azasteroid analogs were developed with the potential to inhibit 3β-HSD, and their metabolic stability and and inhibitory activity against were investigated. Pharmacologic properties indicated lower metabolic liabilities for azasteroid in comparison to its progenitors, azasteroids and resulting in improved accumulation and extended values in mice. Azasteroid also partially inhibits 3β-HSD . When tested in the Shepard's mouse footpad model of leprosy, azasteroid showed effective bacterial killing that was accelerated when combined with a subinhibitory dose of rifampicin and exhibited an absence of detectable hepatotoxic effects. We concluded that 6-azasteroids derivatives are promising new antimicrobial candidates for leprosy treatment.IMPORTANCELeprosy remains a significant global health challenge, particularly in underserved regions. While multidrug therapy (MDT) has been effective, its prolonged duration and the emergence of antibiotic-resistant strains emphasize the urgent need for novel therapeutic strategies. Recent advances in understanding 's unique biology have identified cholesterol metabolism as a critical pathway for bacterial survival and pathogenesis, offering a promising new target for drug development. Building on insights from tuberculosis research, azasteroids-compounds known for their potential to disrupt mycobacterial cholesterol metabolism-are now being explored as candidates for leprosy treatment. These molecules inhibit 's cholesterol oxidation, impairing bacterial persistence within the host. This innovative approach could lead to more effective, faster-acting therapies, overcoming current treatment limitations and resistance. Such efforts represent a vital step forward in reducing the burden of leprosy and empowering affected communities worldwide.
尽管目前用于治疗麻风病的多药疗法（MDT）非常成功，但治疗时间长以及抗生素耐药菌株的出现促使人们寻找新的替代药物。开发抗致病性分枝杆菌药物的一个潜在靶点是它们在感染过程中降解宿主胆固醇的需求。由于其基因组退化，[某种细菌名称]仅保留了胆固醇分解代谢的第一步，即胆固醇被3β-羟基类固醇脱氢酶（3β-HSD）氧化为胆甾烯酮。[某种细菌名称]大量产生胆甾烯酮，这种代谢活性似乎在细菌致病过程中起重要作用。在本研究中，开发了六种具有抑制3β-HSD潜力的6-氮杂甾体类似物，并研究了它们的代谢稳定性以及对[某种细菌名称]的抑制活性。药理学特性表明，与它的前体氮杂甾体[具体名称1]和[具体名称2]相比，氮杂甾体[具体名称3]的代谢负担更低，这导致其在小鼠体内的蓄积改善且半衰期延长。氮杂甾体[具体名称4]也部分抑制[某种细菌名称]的3β-HSD。在麻风病的谢泼德小鼠足垫模型中进行测试时，氮杂甾体[具体名称5]显示出有效的杀菌作用，当与亚抑制剂量的利福平联合使用时杀菌作用加速，并且未表现出可检测到的肝毒性作用。我们得出结论，6-氮杂甾体衍生物是有前景的用于麻风病治疗的新型抗菌候选药物。
重要性
麻风病仍然是一项重大的全球健康挑战，特别是在医疗服务不足的地区。虽然多药疗法（MDT）一直有效，但其疗程长以及抗生素耐药菌株的出现凸显了对新型治疗策略的迫切需求。对[某种细菌名称]独特生物学特性的最新认识进展已将胆固醇代谢确定为细菌存活和致病的关键途径，为药物开发提供了一个有前景的新靶点。基于结核病研究的见解，氮杂甾体——以其破坏分枝杆菌胆固醇代谢的潜力而闻名的化合物——现在正被探索作为麻风病治疗的候选药物。这些分子抑制[某种细菌名称]的胆固醇氧化，损害细菌在宿主体内的持久性。这种创新方法可能会带来更有效、作用更快的疗法，克服当前治疗的局限性和耐药性。这些努力是在减轻麻风病负担和增强全球受影响社区能力方面向前迈出的重要一步。
