Development of Novel Therapeutics for Treatment of Mycobacterial Infections

氨基糖苷类化合物(AG)对革兰氏阳性菌和革兰氏阴性菌具有广泛的抗菌谱。 和分枝杆菌病原体。AG的毒性包括肾小管坏死、眩晕，最显著的是听力 损失。关于AG在分枝杆菌感染中的应用，它们被用来治疗多重耐药 结核和脓肿分枝杆菌复合体(MABSC)感染囊性纤维化患者 (或其他结构性肺部疾病)。研究表明，55%-58%的耐多药结核病患者 作为他们治疗的一部分，接受了阿米卡星的治疗，由于其耳毒性作用，经历了听力损失。同样，高达 27%接受氨基糖苷类药物治疗的感染脓肿支原体的囊性纤维化患者 经历了听力损失。到目前为止，还没有FDA批准的方法或疗法来预防或 治疗听力损失。减少对氨基糖苷类药物在分枝杆菌感染中使用的依赖应尽量减少 感染耐药结核分枝杆菌(M.TB)菌株和 非结核(NTM)分枝杆菌。 我们已经发现了一系列新的小分子(吲哚-2-甲酰胺和乙酰胺)，它们具有强大的 对一组分枝杆菌的活性。我们的两名主要候选人的口语吸收能力较差，但成绩尚不理想。 在脓肿支原体感染小鼠模型中的疗效。因此，我们建议发现和开发抗分枝杆菌。 具有强大活性的抑制剂，具有改善的药代动力学特征，并且没有耳毒性。这将是 使用基于配体的药物设计和计算机辅助药物设计来完成。体外生物利用度和 还将确定这些抑制剂的毒性分布。最后，优化了有效的抗NTM药物 生物利用度和毒性分布将受到大分子作用机制研究的影响，确保 未来的化合物仍将作为分枝杆菌膜蛋白大分子3(MmpL3)的抑制剂。

Aminoglycosides (AG) have broad antibiotic spectra against aerobic gram-positive and gram-negative bacteria and mycobacterial pathogens. AG toxicities include kidney tubular necrosis, vertigo, and, most notably, hearing loss. Regarding the use of AG in mycobacterial infections, they are used to treat multidrug-resistant tuberculosis (MDR-TB) and Mycobacterium abscessus complex (MABSC) infected patients with cystic fibrosis (or other structural lung disorders). Studies have shown that 55-58% of patients infected with MDR-TB who received amikacin as part of their therapy, experienced hearing loss due to its ototoxic effects. Likewise, up to 27% of patients with cystic fibrosis infected with M. abscessus who received aminoglycoside therapy experienced hearing loss. To date, there is no FDA-approved method or therapy available to prevent or treat hearing loss. Reduced reliance on aminoglycoside use in mycobacterial infections should minimize hearing loss risk for patients infected with drug-resistant Mycobacterium tuberculosis (M. tb) strains and nontuberculous (NTM) mycobacteria. We have discovered a novel series of small molecules (indole-2-carboxamides and acetamides) that have potent activity against a panel of mycobacteria. Two of our lead candidates had poor oral absorption yet achieved efficacy in a mouse model of M. abscessus infection. Therefore, we propose to discover and develop antimycobacterial inhibitors with potent activity with improved pharmacokinetic profiles and no ototoxicity. This will be accomplished using ligand-based drug design and computer aided drug design. In vitro bioavailability and toxicity profiles will also be determined for the inhibitors. Finally, potent anti-NTM agents with optimized bioavailability and toxicity profiles will be subjected to macromolecular mechanism of action studies, ensuring future compounds remain on target as Mycobacterial membrane protein Large 3 (MmpL3) inhibitors.