Mugnaini Claudia, Sannio Filomena, Brizzi Antonella, Del Prete Rosita, Simone Tiziana, Ferraro Teresa, De Luca Filomena, Corelli Federico, Docquier Jean-Denis
Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Aldo Moro 2, 53100 Siena, Italy.
Dipartimento di Biotecnologie Mediche, Università degli Studi di Siena, Viale Bracci 16, 53100 Siena, Italy.
ACS Med Chem Lett. 2020 Mar 6;11(5):899-905. doi: 10.1021/acsmedchemlett.9b00674. eCollection 2020 May 14.
Antibiotic resistance is an increasingly important global public health issue, as major opportunistic pathogens are evolving toward multidrug- and pan-drug resistance phenotypes. New antibiotics are thus needed to maintain our ability to treat bacterial infections. According to the WHO, carbapenem-resistant , , and are the most critical targets for the development of new antibacterial drugs. An automated phenotypic screen was implemented to screen 634 synthetic compounds obtained in-house for both their direct-acting and synergistic activity. Fourteen percent and 10% of the compounds showed growth inhibition against tested Gram-positive and Gram-negative bacteria, respectively. The most active direct-acting compounds showed a broad-spectrum antibacterial activity, including on some multidrug-resistant clinical isolates. In addition, 47 compounds were identified for their ability to potentiate the activity of other antibiotics. Compounds of three different scaffolds (2-quinolones, phenols, and pyrazoles) showed a strong potentiation of colistin, some being able to revert colistin resistance in .
抗生素耐药性是一个日益重要的全球公共卫生问题，因为主要的机会性病原体正在朝着多重耐药和泛耐药表型演变。因此，需要新的抗生素来维持我们治疗细菌感染的能力。根据世界卫生组织的说法，耐碳青霉烯类肠杆菌科细菌、鲍曼不动杆菌和铜绿假单胞菌是开发新型抗菌药物的最关键目标。实施了一项自动化表型筛选，以筛选内部获得的634种合成化合物的直接作用和协同活性。分别有14%和10%的化合物对测试的革兰氏阳性菌和革兰氏阴性菌表现出生长抑制作用。最具活性的直接作用化合物表现出广谱抗菌活性，包括对一些多重耐药临床分离株。此外，鉴定出47种化合物具有增强其他抗生素活性的能力。三种不同支架（2-喹诺酮类、酚类和吡唑类）的化合物对黏菌素表现出强烈的增效作用，有些能够恢复肺炎克雷伯菌对黏菌素的耐药性。
