Hytramycins V and I, Anti-Mycobacterium tuberculosis Hexapeptides from a Streptomyces hygroscopicus Strain

详细信息    查看全文

• 作者：Geping Cai ; Jos茅 G. Napolitano ; James B. McAlpine ; Yuehong Wang ; Birgit U. Jaki ; Joo-Won Suh ; Seung Hwan Yang ; In-Ae Lee ; Scott G. Franzblau ; Guido F. Pauli ; Sanghyun Cho
• 刊名：Journal of Natural Products
• 出版年：2013
• 出版时间：November 22, 2013
• 年：2013
• 卷：76
• 期：11
• 页码：2009-2018
• 全文大小：438K
• 年卷期：v.76,no.11(November 22, 2013)
• ISSN：1520-6025

文摘

Thirty-five thousand actinomycete extracts were screened for anti-Mycobacterium tuberculosis (M. tb) activity, followed by C₁₈ cartridge fractionation of 37 prioritized extracts. Based on MICs against replicating and nonreplicating M. tb, and IC₅₀ values against Vero cells to generate selectivity indices, seven fractions from seven different strains were selected for further examination. When cultured in G.S.S. media and extracted with ethyl acetate, the Streptomyces hygroscopicus strain ECUM 14046 yielded an extract with promising anti-M. tb activity and a well-defined chromatographic profile. Fractionation by preparative HPLC and subsequent structure elucidation of two active fractions using 1D- and 2D-NMR and MS methods revealed the presence of two cyclohexapeptides, hytramycins V and I, each containing three unusual piperazic acid moieties. The use of ¹H iterative full spin analysis (HiFSA) on both hytramycins confirmed that quantum mechanics-simulated spectra match the experimental data, and all J_H,H and 未_H values are consistent with the proposed structures. The absolute configuration of each amino acid moiety was determined by Marfey鈥檚 method. The MICs against replicating and, more importantly, nonreplicating M. tb fall into the range of some existing second-line anti-TB drugs, such as streptomycin and capreomycin, respectively. The activities were maintained against M. tb strains that represent the major global clades, as well as H₃₇Rv-isogenic strains that are resistant to individual clinical anti-TB drugs.