Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA.
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USA.
Mar Drugs. 2012 Apr;10(4):953-962. doi: 10.3390/md10040953. Epub 2012 Apr 24.
Infections caused by drug-resistant pathogens are on the rise. The ongoing spread of methicillin-resistant Staphylococcus aureus (MRSA) strains exemplifies the urgent need for new antibiotics. The marine natural product, marinopyrrole A, was previously shown to have potent antibiotic activity against Gram-positive pathogens, including MRSA. However, its minimum inhibitory concentration (MIC) against MRSA was increased by >500 fold in the presence of 20% human serum, thus greatly limiting therapeutic potential. Here we report our discovery of a novel derivative of marinopyrrole A, designated 1a, featuring a 2-4 fold improved MIC against MRSA and significantly less susceptibility to serum inhibition. Importantly, compound 1a displayed rapid and concentration-dependent killing of MRSA. Compared to the natural product counterpart, compound 1a provides an important natural product based scaffold for further Structure Activity Relationship (SAR) and optimization.
耐药病原体引起的感染正在上升。耐甲氧西林金黄色葡萄球菌（MRSA）菌株的持续传播就是一个迫切需要新型抗生素的例子。海洋天然产物 marinopyrrole A 先前显示出对革兰氏阳性病原体（包括 MRSA）具有强大的抗生素活性。然而，当存在 20%的人血清时，它对 MRSA 的最小抑菌浓度（MIC）增加了>500 倍，从而大大限制了其治疗潜力。在这里，我们报告了我们对 marinopyrrole A 的一种新型衍生物 1a 的发现，其对 MRSA 的 MIC 提高了 2-4 倍，对血清抑制的敏感性显著降低。重要的是，化合物 1a 对 MRSA 表现出快速和浓度依赖性的杀伤作用。与天然产物相对照，化合物 1a 为进一步的结构活性关系（SAR）和优化提供了一个重要的天然产物骨架。
