Combining cancer chemotherapeutics with bacterial DNA repair inhibitors to develop novel antimicrobials

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.

癌症化疗药物会杀死快速分裂的细胞，其中包括免疫系统的细胞。由此导致的中性粒细胞减少使患者易受感染，这会延误治疗，并且是发病和死亡的主要原因。在此，我们利用抗癌化合物顺铂的细胞毒性来筛选美国食品药品监督管理局（FDA）批准的、会损害细菌核苷酸切除修复（NER）的药物，NER是细菌修复顺铂损伤的主要机制。有五种化合物脱颖而出，其中三种具有理想的抗菌特性，包括细胞穿透性、对NER的特异性活性以及杀死具有多重耐药性且与临床相关的大肠杆菌菌株的能力。针对NER，通过将抗菌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。