Cho Hyejin, Kim Kwang-Sun
Department of Chemistry and Chemistry Institute for Functional Materials, Pusan National University, Busan 46241, Korea.
Pharmaceutics. 2022 Mar 1;14(3):552. doi: 10.3390/pharmaceutics14030552.
Multidrug-resistant (MDR) Gram-negative bacteria are the top-priority pathogens to be eradicated. Drug repurposing (e.g., the use of non-antibiotics to treat bacterial infections) may be helpful to overcome the limitations of current antibiotics. Zidovudine (azidothymidine, AZT), a licensed oral antiviral agent, is a leading repurposed drug against MDR Gram-negative bacterial infections. However, the rapid emergence of bacterial resistance due to long-term exposure, overuse, or misuse limits its application, making it necessary to develop new alternatives. In this study, we investigated the efficacy of ciclopirox (CPX) as an alternative to AZT. The minimum inhibitory concentrations of AZT and CPX against MDR Gram-negative bacteria were determined; CPX appeared more active against β-lactamase-producing , whereas AZT displayed no selectivity for any antibiotic-resistant strain. Motility assays revealed that β-lactamase-producing strains were less motile in nature and more strongly affected by CPX than a parental strain. Resistance against CPX was not observed in even after 25 days of growth, whereas AZT resistance was observed in less than 2 days. Moreover, CPX effectively killed AZT-resistant strains with different resistance mechanisms. Our findings indicate that CPX may be utilized as an alternative or supplement to AZT-based medications to treat opportunistic Gram-negative bacterial infections.
多重耐药（MDR）革兰氏阴性菌是需要根除的首要病原体。药物重新利用（例如，使用非抗生素药物治疗细菌感染）可能有助于克服当前抗生素的局限性。齐多夫定（叠氮胸苷，AZT）是一种已获许可的口服抗病毒药物，是对抗多重耐药革兰氏阴性菌感染的主要重新利用药物。然而，由于长期接触、过度使用或滥用导致细菌耐药性迅速出现，限制了其应用，因此有必要开发新的替代药物。在本研究中，我们研究了环吡酮（CPX）作为AZT替代药物的疗效。测定了AZT和CPX对多重耐药革兰氏阴性菌的最低抑菌浓度；CPX对产β-内酰胺酶的菌株表现出更强的活性，而AZT对任何抗生素耐药菌株均无选择性。运动性试验表明，产β-内酰胺酶的菌株本身运动性较差，且比亲本菌株更易受CPX影响。即使生长25天后， 对CPX仍未产生耐药性，而不到2天就观察到了对AZT的耐药性。此外，CPX能有效杀灭具有不同耐药机制的AZT耐药菌株。我们的研究结果表明，CPX可作为基于AZT的药物的替代药物或补充药物，用于治疗机会性革兰氏阴性菌感染。
