Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States.
Department of Microbiology & Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755, United States.
J Med Chem. 2022 Oct 27;65(20):13910-13934. doi: 10.1021/acs.jmedchem.2c01151. Epub 2022 Oct 11.
Nosocomial infections caused by resistant Gram-positive organisms are on the rise, presumably due to a combination of factors including prolonged hospital exposure, increased use of invasive procedures, and pervasive antibiotic therapy. Although antibiotic stewardship and infection control measures are helpful, newer agents against multidrug-resistant (MDR) Gram-positive bacteria are urgently needed. Here, we describe our efforts that led to the identification of 5-amino-4-quinolone with exceptionally potent Gram-positive activity with minimum inhibitory concentrations (MICs) ≤0.06 μg/mL against numerous clinical isolates. Preliminary mechanism of action and resistance studies demonstrate that the 5-amino-4-quinolones are bacteriostatic, do not select for resistance, and selectively disrupt bacterial membranes. While the precise molecular mechanism has not been elucidated, the lead compound is nontoxic displaying a therapeutic index greater than 500, is devoid of hemolytic activity, and has attractive physicochemical properties (clog = 3.8, molecular weight (MW) = 441) that warrant further investigation of this promising antibacterial scaffold for the treatment of Gram-positive infections.
耐革兰阳性菌引起的医院感染呈上升趋势，推测这与多种因素有关，包括住院时间延长、侵入性操作增加和广泛使用抗生素治疗。虽然抗生素管理和感染控制措施是有帮助的，但迫切需要新的针对多药耐药（MDR）革兰阳性菌的药物。在这里，我们描述了我们的努力，这些努力导致了发现了具有异常强大的革兰阳性活性的 5-氨基-4-喹诺酮，对许多临床分离株的最低抑菌浓度（MIC）≤0.06μg/mL。初步的作用机制和耐药性研究表明，5-氨基-4-喹诺酮类是抑菌剂，不会选择耐药性，并且选择性地破坏细菌膜。虽然精确的分子机制尚未阐明，但先导化合物无毒性，治疗指数大于 500，无溶血活性，具有有吸引力的物理化学性质（ clog = 3.8，分子量（MW）= 441），这证明了该有希望的抗菌骨架用于治疗革兰阳性感染的进一步研究是合理的。
