Krembil Research Institute, University Health Network, University of Toronto, Toronto, ON, Canada.
Department of Pharmacology, Dalhousie University, Halifax, NS, Canada.
Nat Commun. 2024 Sep 27;15(1):8317. doi: 10.1038/s41467-024-52797-2.
The World Health Organization has identified antibiotic resistance as one of the three greatest threats to human health. The need for antibiotics is a pressing matter that requires immediate attention. Here, computer-aided drug design is used to develop a structurally unique antibiotic family targeting holo-acyl carrier protein synthase (AcpS). AcpS is a highly conserved enzyme essential for bacterial survival that catalyzes the first step in lipid synthesis. To the best of our knowledge, there are no current antibiotics targeting AcpS making this drug development program of high interest. We synthesize a library of > 700 novel compounds targeting AcpS, from which 33 inhibit bacterial growth in vitro at ≤ 2 μg/mL. We demonstrate that compounds from this class have stand-alone activity against a broad spectrum of Gram-positive organisms and synergize with colistin to enable coverage of Gram-negative species. We demonstrate efficacy against clinically relevant multi-drug resistant strains in vitro and in animal models of infection in vivo including a difficult-to-treat ischemic infection exemplified by diabetic foot ulcer infections in humans. This antibiotic family could form the basis for several multi-drug-resistant antimicrobial programs.
世界卫生组织已将抗生素耐药性确定为对人类健康的三大威胁之一。对抗生素的需求是一个紧迫的问题，需要立即引起关注。在这里，我们使用计算机辅助药物设计来开发一种针对酰基辅酶 A 合成酶（AcpS）的结构独特的抗生素家族。AcpS 是一种高度保守的酶，对于细菌的生存至关重要，它催化脂质合成的第一步。据我们所知，目前没有针对 AcpS 的抗生素，因此，这项药物开发计划具有很高的研究价值。我们合成了一个针对 AcpS 的新型化合物库，其中 33 个化合物在体外以≤2μg/ml 的浓度抑制细菌生长。我们证明，这类化合物具有独立的活性，能够对抗广泛的革兰氏阳性菌，并与黏菌素协同作用，覆盖革兰氏阴性菌。我们在体外和体内感染模型中证明了该抗生素家族对临床相关的多药耐药菌株的疗效，包括在人类糖尿病足溃疡感染等难以治疗的缺血性感染中。这个抗生素家族可以成为几种多药耐药抗菌药物方案的基础。
