Development of Novel Therapeutics for Treatment of Mycobacterial Infections

氨基糖苷类抗生素对需氧革兰氏阳性菌和革兰氏阴性菌具有广谱抗菌作用 和分枝杆菌病原体。AG毒性包括肾小管坏死、眩晕，最明显的是听力 损失关于AG在分枝杆菌感染中的使用，它们用于治疗多药耐药的 结核病（MDR-TB）和结核分枝杆菌复合体（MABSC）感染的囊性纤维化患者 (or其他结构性肺病）。研究表明，55-58%的耐多药结核病患者， 接受阿米卡星作为其治疗的一部分，由于其耳毒性作用而出现听力损失。同样，直到 27%的囊性纤维化患者感染M.接受氨基糖苷类药物治疗的患者 经历听力损失。到目前为止，没有FDA批准的方法或疗法可用于预防或治疗。 治疗听力损失。在分枝杆菌感染中减少对氨基糖苷类药物的依赖， 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）， 对一组分枝杆菌的活性。我们的两个主要候选人口服吸收差，但达到了 在M.尿道感染。因此，我们建议发现和开发抗分枝杆菌药物， 具有有效活性的抑制剂，具有改善的药代动力学特征并且无耳毒性。这将 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 还将测定抑制剂的毒性分布。最后，有效的抗NTM剂与优化 生物利用度和毒性特征将进行大分子作用机制研究，确保 未来的化合物仍然是分枝杆菌膜蛋白Large 3（MmpL 3）抑制剂的目标。

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.