Optimization of 4-Substituted Benzenesulfonamide Scaffold To Reverse Acinetobacter baumannii Serum-Adaptive Efflux Associated Antibiotic Tolerance.
Optimization of 4-Substituted Benzenesulfonamide Scaffold To Reverse Acinetobacter baumannii Serum-Adaptive Efflux Associated Antibiotic Tolerance.
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DOI：
10.1002/cmdc.202000328
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发表时间：
2020-09-16
期刊：
影响因子：
3.4
通讯作者：
Flaherty DP
中科院分区：
文献类型：
--
作者：
Chojnacki M;Cao X;Young M;Fritz RN;Dunman PM;Flaherty DP
鲍曼不动杆菌是一种医院感染的病原菌，由于其多药耐药和泛药耐药率的上升，引起了公众的关注。在环境线索的背景下，如在人类血清中的生长，A。已知鲍曼不动杆菌表现出适应性外排，其中大量外排相关基因被上调，导致外排介导的对抗生素治疗敏感的菌株的药物耐受性。以前，我们鉴定了一种含磺胺的支架分子（ABEPI1），它可以逆转A.鲍曼不动杆菌。在此，我们提出了29个新合成的类似物的构效关系研究。这些分子的特征在于它们能够增强血清中的多种抗生素，减少血清相关的溴化乙锭流出和使细菌细胞膜脱附。此外，还评估了它们对哺乳动物细胞的毒性。总的来说，这些分子可能代表了与新的和现有的抗生素组合使用来治疗A.鲍曼不动杆菌感染。不再躲藏：在溶原肉汤中培养的鲍曼不动杆菌对米诺环素敏感，但在人血清中，细菌上调外排泵，不再对药物敏感。本文描述了在A.在人血清中生长的鲍曼不动杆菌。
Acinetobacter baumannii is a nosocomial pathogen of urgent concern for public health due to rising rates of multidrug and pandrug resistance. In the context of environmental cues such as growth in human serum, A. baumannii is known to display adaptive efflux, in which a multitude of efflux-associated genes are upregulated, resulting in efflux-mediated drug tolerance in strains that are otherwise susceptible to antibiotic therapy. Previously, we identified a sulfonamide-containing scaffold molecule (ABEPI1) that reversed serum-associated antibiotic tolerance in A. baumannii. Herein, we present structure-activity relationship studies on 29 newly synthesized analogues. These molecules were characterized for their ability to potentiate multiple antibiotics in serum, reduce serum-associated ethidium bromide efflux and depolarize bacterial cell membranes. In addition, they were assessed for toxicity to mammalian cells. Collectively, these molecules may represent promising potential adjuvants for use in combination with new and existing antibiotics to treat A. baumannii bacterial infections. No hiding here anymore: Acinetobacter baumannii cultured in lysogeny broth is susceptible to minocycline, but in human serum the bacteria upregulates efflux pumps and is no longer susceptible to the drug. This manuscript describes the optimization of analogues that restore minocycline activity in A. baumannii grown in human serum.
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