Singh Sheo B, Xu Libo, Meinke Peter T, Kurepina Natalia, Kreiswirth Barry N, Olsen David B, Young Katherine
Discovery Chemistry, MRL, Merck & Co., Inc., Kenilworth, NJ, USA.
Discovery Chemistry, MRL, Merck & Co., Inc., Rahway, NJ, USA.
J Antibiot (Tokyo). 2017 May;70(5):671-674. doi: 10.1038/ja.2016.165. Epub 2017 Jan 18.
Thiazolyl peptides are a class of natural products with potent Gram-positive antibacterial activities. Lack of aqueous solubility precluded this class of compounds from advancing to clinical evaluations. Nocathiacins and thiazomycins are sub-classes of thiazolyl peptides that are endowed with structural features amenable for chemical modifications. Semi-synthetic modifications of nocathiacin led to a series of analogs with improved water solubility, while retaining potency and antibacterial spectrum. We studied the activities of a selection of two natural products (nocathiacin and thiazomycin) as well as seven polar semi-synthetic analogs against twenty clinical strains of Mycobacterium tuberculosis with MDR phenotypes. Two compounds show useful activity against H37Rv strain with MIC values ⩽1 μM, two (⩽0.5 μm) and three (⩽10 μm). These two derivatives showed MIC values ⩽2.5 μm against most of the 20 MDR strains regardless their resistance profile. Specifically, these lack cross-resistance to rifampicin, isoniazid and moxifloxacin.
噻唑基肽是一类具有强大革兰氏阳性抗菌活性的天然产物。缺乏水溶性阻碍了这类化合物进入临床评估阶段。诺卡硫辛和噻唑霉素是噻唑基肽的亚类，它们具有适合化学修饰的结构特征。诺卡硫辛的半合成修饰产生了一系列具有改善水溶性的类似物，同时保留了效力和抗菌谱。我们研究了两种天然产物（诺卡硫辛和噻唑霉素）以及七种极性半合成类似物对二十株具有耐多药表型的结核分枝杆菌临床菌株的活性。两种化合物对H37Rv菌株显示出有效的活性，MIC值≤1 μM，两种（≤0.5 μm）和三种（≤10 μm）。这两种衍生物对20株耐多药菌株中的大多数显示出≤2.5 μm的MIC值，无论其耐药情况如何。具体而言，它们对利福平、异烟肼和莫西沙星缺乏交叉耐药性。
