Combining cancer chemotherapeutics with bacterial DNA repair inhibitors to develop novel antimicrobials
Combining cancer chemotherapeutics with bacterial DNA repair inhibitors to develop novel antimicrobials
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DOI：
10.1101/2023.03.17.532951
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发表时间：
2023-03
期刊：
影响因子：
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通讯作者：
L. Bernacchia;Arya Gupta;A. Paris;Alexandra A. Moores;N. Kad
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文献类型：
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作者：
L. Bernacchia;Arya Gupta;A. Paris;Alexandra A. Moores;N. Kad
癌症化疗药物杀死快速分裂的细胞，其中包括免疫系统的细胞。由此产生的中性粒细胞减少症使患者易于感染，从而延迟治疗并且是发病率和死亡率的主要原因。在这里，我们利用抗癌化合物顺铂的细胞毒性来筛选FDA批准的损害细菌核苷酸切除DNA修复（NER）的药物，这是细菌用于修复顺铂病变的主要机制。已经出现了五种化合物，其中三种具有理想的抗菌性能，包括细胞杀灭率，对NER的特异性活性，以及杀死多药耐药临床相关E.大肠杆菌菌株。靶向NER通过将抗微生物活性与癌症化疗相结合，为癌症患者的感染提供了一种新的治疗方法。
Cancer chemotherapeutics kill rapidly dividing cells, which includes cells of the immune system. The resulting neutropenia predisposes patients to infection, which delays treatment and is a major cause of morbidity and mortality. Here we have exploited the cytotoxicity of the anti-cancer compound cisplatin to screen for FDA-approved drugs that impair bacterial nucleotide excision DNA repair (NER), the primary mechanism bacteria use to repair cisplatin lesions. Five compounds have emerged of which three possess ideal antimicrobial properties including cell penetrance, specific activity for NER, and the ability to kill a multi-drug resistant clinically relevant E. coli strain. Targeting NER offers a new therapeutic approach for infections in cancer patients by combining antimicrobial activity with cancer chemotherapy.