Jones Chelsea R, Lai Grant H, Padilla Maria Sophia Teresa Lee, Nowick James S
Department of Chemistry, University of California, Irvine, Irvine, California 92697, United States.
Department of Pharmaceutical Sciences, University of California, Irvine, Irvine, California 92697, United States.
ACS Med Chem Lett. 2024 Jun 11;15(7):1136-1142. doi: 10.1021/acsmedchemlett.4c00215. eCollection 2024 Jul 11.
Although teixobactin is a promising antibiotic drug candidate against Gram-positive bacteria, it aggregates to form gels that may limit intravenous administration. We previously reported -acyl isopeptide prodrugs of teixobactin analogues that address the problem of gel formation while retaining antibiotic activity. We termed these compounds . In the current Letter, we present nine new isobactin analogues that exhibit a reduced propensity to form gels in aqueous conditions while maintaining potent antibiotic activity against MRSA, VRE, and other Gram-positive bacteria. These isobactin analogues contain commercially available amino acid residues at position 10, replacing the synthetically challenging l--enduracididine residue that is present in teixobactin. The isobactins undergo clean conversion to their corresponding teixobactin analogues at physiological pH and exhibit little to no hemolytic activity or cytotoxicity. Because isobactin analogues exhibit enhanced solubility, delayed gel formation, and are more synthetically accessible, it is anticipated that isobactin prodrug analogues may be superior drug candidates to teixobactin.
尽管替考拉宁是一种很有前景的抗革兰氏阳性菌的抗生素药物候选物，但它会聚集形成凝胶，这可能会限制静脉给药。我们之前报道了替考拉宁类似物的 - 酰基异肽前药，它们解决了凝胶形成问题，同时保留了抗生素活性。我们将这些化合物称为 。在当前的信函中，我们展示了九种新的异杆菌素类似物，它们在水性条件下形成凝胶的倾向降低，同时对耐甲氧西林金黄色葡萄球菌（MRSA）、耐万古霉素肠球菌（VRE）和其他革兰氏阳性菌保持强大的抗生素活性。这些异杆菌素类似物在第10位含有市售氨基酸残基，取代了替考拉宁中存在的合成挑战性较大的L - 持久霉素残基。异杆菌素在生理pH值下可干净地转化为其相应的替考拉宁类似物，并且几乎没有溶血活性或细胞毒性。由于异杆菌素类似物具有增强的溶解性、延迟的凝胶形成，并且在合成上更容易获得，预计异杆菌素前药类似物可能是比替考拉宁更优越的药物候选物。
