Experimental Therapeutics Centre, Agency for Science, Technology and Research (A*STAR), 31 Biopolis Way, Nanos #03-01, Singapore, 138669, Singapore.
Department of Laboratory Medicine, National University Hospital, 5 Lower Kent Ridge Road, Singapore, 119074, Singapore.
Eur J Clin Microbiol Infect Dis. 2018 Jan;37(1):141-148. doi: 10.1007/s10096-017-3114-5. Epub 2017 Oct 10.
The global emergence of carbapenem-resistant Enterobacteriaceae (CRE) presents a significant clinical concern, prompting the WHO to prioritize CRE as a top priority pathogen in their 2017 global antibiotic-resistant bacteria priority list. Due to the fast-depleting antibiotic arsenal, clinicians are now resorting to using once-abandoned, highly toxic antibiotics such as the polymyxins and aminoglycosides, creating an urgent need for new antibiotics. Drug repurposing, the application of an approved drug for a new therapeutic indication, is deemed a plausible solution to this problem. A total of 1,163 FDA-approved drugs were screened for activity against a clinical carbapenem- and multidrug-resistant E. coli isolate using a single-point 10 μM assay. Hit compounds were then assessed for their suitability for repurposing. The lead candidate was then tested against a panel of clinical CREs, a bactericidal/static determination assay, a time-kill assay and a checkerboard assay to evaluate its suitability for use in combination with Tigecycline against CRE infections. Three drugs were identified. The lead candidate was determined to be Zidovudine (azidothymidine/AZT), an oral anti-viral drug used for HIV treatment. Zidovudine was shown to be the most promising candidate for use in combination with Tigecycline to treat systemic CRE infections. Further experiments should involve the use of animal infection models.
全球范围内出现的碳青霉烯类耐药肠杆菌科（CRE）引起了重大的临床关注，促使世界卫生组织（WHO）在其 2017 年全球抗生素耐药菌优先清单中将 CRE 列为头号优先病原体。由于抗生素储备迅速减少，临床医生现在不得不重新使用曾经被弃用的、高度毒性的抗生素，如多黏菌素和氨基糖苷类，因此迫切需要新的抗生素。药物再利用，即将已批准的药物用于新的治疗适应症，被认为是解决这一问题的可行方法。使用单点 10 μM 测定法，对 1163 种 FDA 批准的药物进行了针对临床碳青霉烯类和多药耐药大肠杆菌分离株的活性筛选。然后评估了候选化合物的再利用适用性。然后对候选药物进行了一系列的临床 CRE 试验、杀菌/抑菌测定试验、时间杀伤试验和棋盘试验，以评估其与替加环素联合用于治疗 CRE 感染的适用性。鉴定出三种药物。候选药物被确定为齐多夫定（叠氮胸苷/AZT），这是一种用于 HIV 治疗的口服抗病毒药物。齐多夫定被证明是与替加环素联合治疗全身性 CRE 感染最有前途的候选药物。进一步的实验应涉及使用动物感染模型。
