Bacteriology & Antibacterial Resistance Surveillance Laboratory, Shenzhen Institute of Respiratory Diseases, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China.
Intensive Care Unit, Shenzhen People's Hospital(The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China.
J Antibiot (Tokyo). 2021 May;74(5):324-329. doi: 10.1038/s41429-020-00401-2. Epub 2021 Jan 18.
The threat of antimicrobial resistance calls for more efforts in basic science, drug discovery, and clinical development, particularly gram-negative carbapenem-resistant pathogens. We sought to identify novel antibacterial agents against Acinetobacter baumannii ATCC19606 using whole cell-based screening. A small molecule named 6D1 with the chemical structure of 6-fluorobenzo[d]isothiazol-3(2H)-one was identified and exhibited activity against A. baumannii ATCC19606 strain (minimal inhibitory concentration, MIC = 1 mg l). The mutation in the plasmid-derived ohrB gene that encodes a peroxidase was identified in spontaneously resistant mutants. Treatment of the bacteria with 6D1 resulted in increased sensitivity to peroxide, such as tert-butyl hydroperoxide. The binding of 6D1 and OhrB was confirmed by surface plasmon resonance. Interestingly, the MIC of kanamycin and gentamicin against spontaneously resistant mutants decreased. Finally, we identified the effect of 6D1 on enhancing the antibacterial activity of kanamycin and gentamicin, including against New Delhi metallo-β-lactamase (NDM-1)-producing carbapenem-resistant Klebsiella pneumoniae, but not in strains carrying aminoglycosides resistance genes. In this study, we identified a small molecule that suppresses the growth of A. baumannii, interacts with hydroperoxide reductase from A. baumannii ATCC19606 plasmid pMAC, and enhances the antibacterial activity of kanamycin and gentamicin. We propose that peroxidase may be potentially used as a target for aminoglycosides adjuvant development.
耐抗生素药物的威胁需要在基础科学、药物发现和临床开发方面投入更多的努力，特别是针对革兰氏阴性碳青霉烯类耐药病原体。我们试图使用全细胞筛选来寻找针对鲍曼不动杆菌 ATCC19606 的新型抗菌剂。鉴定出一种名为 6D1 的小分子，其化学结构为 6-氟苯并[d]异噻唑-3(2H)-酮，对鲍曼不动杆菌 ATCC19606 菌株具有活性（最小抑菌浓度，MIC = 1 mg l）。在自发耐药突变体中鉴定出编码过氧化物酶的质粒衍生 ohrB 基因的突变。用 6D1 处理细菌会导致对过氧化物（如叔丁基过氧化氢）的敏感性增加。表面等离子体共振证实了 6D1 与 OhrB 的结合。有趣的是，卡那霉素和庆大霉素对自发耐药突变体的 MIC 降低。最后，我们确定了 6D1 对增强卡那霉素和庆大霉素抗菌活性的影响，包括对产生新德里金属-β-内酰胺酶（NDM-1）的耐碳青霉烯类肺炎克雷伯菌，但对携带氨基糖苷类耐药基因的菌株没有影响。在这项研究中，我们鉴定出一种小分子，它可以抑制鲍曼不动杆菌的生长，与鲍曼不动杆菌 ATCC19606 质粒 pMAC 的过氧化物还原酶相互作用，并增强卡那霉素和庆大霉素的抗菌活性。我们提出过氧化物酶可能潜在地用作氨基糖苷类药物佐剂开发的靶标。
