Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana 47907, United States.
Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, 625 Harrison Street, West Lafayette, Indiana 47907, United States.
J Med Chem. 2020 Sep 10;63(17):9540-9562. doi: 10.1021/acs.jmedchem.0c00734. Epub 2020 Aug 11.
Vancomycin-resistant enterococci (VRE) are the second leading cause of hospital-acquired infections (HAIs) attributed to a drug-resistant bacterium in the United States, and resistance to the frontline treatments is well documented. To combat VRE, we have repurposed the FDA-approved carbonic anhydrase drug acetazolamide to design potent antienterococcal agents. Through structure-activity relationship optimization we have arrived at two leads possessing improved potency against clinical VRE strains from MIC = 2 μg/mL (acetazolamide) to MIC = 0.007 μg/mL () and 1 μg/mL (). Physicochemical properties were modified to design leads that have either high oral bioavailability to treat systemic infections or low intestinal permeability to treat VRE infections in the gastrointestinal tract. Our data suggest the intracellular targets for the molecules are putative α-carbonic and γ-carbonic anhydrases, and homology modeling and molecular dynamics simulations were performed. Together, this study presents potential anti-VRE therapeutic options to provide alternatives for problematic VRE infections.
耐万古霉素肠球菌（VRE）是美国第二大由耐药菌引起的医院获得性感染（HAI）的原因，而且这种细菌对一线治疗药物的耐药性已有充分的记录。为了对抗 VRE，我们重新利用了美国食品和药物管理局（FDA）批准的碳酸酐酶药物乙酰唑胺来设计有效的抗肠球菌药物。通过结构-活性关系的优化，我们得到了两个具有更高活性的先导化合物，对临床 VRE 菌株的 MIC 值从 2 μg/mL（乙酰唑胺）降低到了 0.007 μg/mL（）和 1 μg/mL（）。我们还对理化性质进行了修饰，设计出了具有高口服生物利用度的先导化合物，用于治疗全身感染，或具有低肠道通透性的先导化合物，用于治疗胃肠道中的 VRE 感染。我们的数据表明，这些分子的细胞内靶标是假定的α-碳酸酐酶和γ-碳酸酐酶，并且进行了同源建模和分子动力学模拟。总的来说，这项研究提出了潜在的抗 VRE 治疗选择，为有问题的 VRE 感染提供了替代方案。
