SQ31f is a potent non-tuberculous mycobacteria antibiotic by specifically targeting the mycobacterial F-ATP synthase.

IF 3.9 2区 医学 Q1 INFECTIOUS DISEASES
Priya Ragunathan, Patcharaporn Sae-Lao, Amaravadhi Harikishore, Wassim Daher, Françoise Roquet-Banères, Laurent Kremer, Roderick W Bates, Gerhard Grüber
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Abstract

Background: Non-tuberculous mycobacteria (NTM) infection presents a growing global health problem and requires new antibiotics targeting enzymes that are essential for the pathogens under various metabolic conditions, with high target specificity, good solubility and with attractive combinatory potency.

Methods: SQ31f was synthesized by a simplified synthesis protocol, and its effect on growth inhibition of fast- and slow-growing NTM and clinical isolates, whole-cell ATP depletion, ex vivo macrophages and its potency in combination with other antibiotics were evaluated. Molecular docking studies were employed to assess SQ31f's binding mode.

Results: We present- squaramide SQ31f as a novel anti-NTM inhibitor targeting the NTM F1FO-ATP synthase, essential for ATP formation, regulation of ATP homeostasis and proton motive force under multiple growth conditions. The potency of SQ31f in growth inhibition of fast- and slow-growing NTM and clinical isolates correlates with whole-cell ATP depletion, which is not caused by altered oxygen consumption. SQ31f's high aqueous solubility enables binding to the waterfilled cytosolic proton half channel in the subunits a-c interface of the FO domain. As presented for the fast-growing Mycobacterium abscessus, the compound is active against intracellular-residing M. abscessus. Importantly, SQ31f shows an additive effect of the anti-M. abscessus drugs clofazimine, rifabutin or amikacin, and an attractive potentiation of linezolid, clarithromycin, or the oral pair tebipenem and avibactam.

Conclusions: SQ31f represents an attractive inhibitor to tackle the issues associated with NTM drug tolerance and toxicity. Its combinatory potency with anti-M. abscessus drugs holds potential for overcoming resistance, while also reducing intensive compound synthesis and associated costs.

SQ31f 是一种特异性靶向分枝杆菌 F-ATP 合成酶的强效非结核分枝杆菌抗生素。
背景:非结核分枝杆菌(NTM)感染是一个日益严重的全球性健康问题,需要针对病原体在各种代谢条件下所必需的酶的新抗生素,这些抗生素必须具有高度的靶向特异性、良好的溶解性和诱人的复合效力:方法:采用简化的合成方案合成了 SQ31f,并评估了它对快速和慢速生长的 NTM 和临床分离株的生长抑制作用、全细胞 ATP 耗竭、体外巨噬细胞以及它与其他抗生素的联合效力。分子对接研究用于评估 SQ31f 的结合模式:结果:我们发现方酰胺 SQ31f 是一种新型的抗 NTM 抑制剂,它靶向 NTM F1FO-ATP 合酶,在多种生长条件下对 ATP 的形成、ATP 稳态调节和质子动力至关重要。SQ31f 对快速和慢速生长的 NTM 和临床分离物的生长抑制作用与全细胞 ATP 耗竭相关,而全细胞 ATP 耗竭并非由耗氧量改变引起。SQ31f 的高水溶性使其能够与 FO 结构域 a-c 亚基界面中充满水的细胞质质子半通道结合。正如针对快速生长的脓肿分枝杆菌所展示的那样,该化合物对细胞内驻留的脓肿分枝杆菌具有活性。重要的是,SQ31f 显示出与抗脓肿分枝杆菌药物氯法齐明、利福布汀或阿米卡星的相加效应,以及与利奈唑胺、克拉霉素或替比培南和阿维巴坦口服组合的诱人增效作用:SQ31f是一种极具吸引力的抑制剂,可解决与NTM药物耐受性和毒性相关的问题。结论:SQ31f 是一种极具吸引力的抑制剂,可解决与 NTM 药物耐受性和毒性相关的问题。它与抗脓毒症药物的联合效力有望克服耐药性,同时还能减少化合物的大量合成并降低相关成本。
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来源期刊
CiteScore
9.20
自引率
5.80%
发文量
423
审稿时长
2-4 weeks
期刊介绍: The Journal publishes articles that further knowledge and advance the science and application of antimicrobial chemotherapy with antibiotics and antifungal, antiviral and antiprotozoal agents. The Journal publishes primarily in human medicine, and articles in veterinary medicine likely to have an impact on global health.
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