Production of Ramoplanin and Ramoplanin Analogs by Actinomycetes.
Production of Ramoplanin and Ramoplanin Analogs by Actinomycetes.
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DOI：
10.3389/fmicb.2017.00343
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发表时间：
2017
影响因子：
5.2
通讯作者：
Vicente F
中科院分区：
文献类型：
--
作者：
de la Cruz M;González I;Parish CA;Onishi R;Tormo JR;Martín J;Peláez F;Zink D;El Aouad N;Reyes F;Genilloud O;Vicente F
Ramoplanin 是一种糖脂缩肽抗生素，从 Actinoplanes sp. 发酵中获得。 ATCC 33076 对临床上重要的多重耐药革兰氏阳性病原体具有活性，包括耐万古霉素肠球菌 (VRE)、耐甲氧西林金黄色葡萄球菌 (MRSA) 和万古霉素中度耐药艰难梭菌。它通过隔离肽聚糖中间体脂质 II 的独特作用机制破坏细菌细胞壁，因此不会与其他抗生素表现出交叉耐药性。然而，虽然雷莫拉宁在感染动物模型中全身使用时表现出优异的抗菌活性，但静脉注射时雷莫拉宁的局部耐受性较低。由于这种限制，需要新的衍生物来克服这个问题。在一项旨在发现通过与中间体脂质 II 结合抑制肽聚糖转糖基化来破坏细菌细胞壁合成的化合物的天然产物筛选计划中，HR-LCMS 鉴定出 49 种放线菌菌株为雷莫拉宁相关化合物的生产者。生产菌株是从世界各地收集的环境样本中分离出来的，包括热带和温带地区。为了评估该微生物种群的多样性，根据微形态学对 49 个分离株进行了属水平初步鉴定，并通过 16S 测序证实了菌株的初步鉴定。这些分析鉴定了链霉菌属的成员，以及小单孢菌科、诺卡氏菌科、嗜热单孢菌科和假诺卡氏菌科的代表，表明雷莫拉宁的生产在放线菌中相对广泛。此外，所有这些分离株都针对一组革兰氏阳性和革兰氏阴性细菌、丝状真菌和酵母进行了测试，以进一步表征它们的抗菌特性。这项工作描述了产生雷莫拉宁相关化合物的放线菌菌株的多样性，以及对这些分离株所表现出的抗菌活性的分析。我们的结果强烈表明这些放线菌生产者中存在新的雷莫拉宁类似物。
Ramoplanin is a glycolipodepsipeptide antibiotic obtained from fermentation of Actinoplanes sp. ATCC 33076 that exhibits activity against clinically important multi-drug-resistant, Gram-positive pathogens including vancomycin-resistant Enterococcus (VRE), methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-intermediate resistant Clostridium difficile. It disrupts bacterial cell wall through a unique mechanism of action by sequestering the peptidoglycan intermediate Lipid II and therefore does not show cross-resistance with other antibiotics. However, while demonstrating excellent antimicrobial activity in systemic use in animal models of infection, ramoplanin presents low local tolerability when injected intravenously. As a consequence of this limitation, new derivatives are desirable to overcome this issue. During a natural product screening program developed to discover compounds that disrupt bacterial cell wall synthesis by inhibiting peptidoglycan transglycosylation through binding to the intermediate Lipid II, 49 actinomycete strains were identified by HR-LCMS as producers of ramoplanin-related compounds. The producing strains were isolated from environmental samples collected worldwide comprising both tropical and temperate areas. To assess the diversity of this microbial population, the 49 isolates were initially identified to the genus level on the basis of their micromorphology, and 16S sequencing confirmed the initial identification of the strains. These analyses resulted in the identification of members of genus Streptomyces, as well as representatives of the families Micromonosporaceae, Nocardiaceae, Thermomonosporaceae, and Pseudonocardiaceae, suggesting that the production of ramoplanins is relatively widespread among Actinomycetes. In addition, all of these isolates were tested against a panel of Gram-positive and Gram-negative bacteria, filamentous fungi, and yeast in order to further characterize their antimicrobial properties. This work describes the diversity of actinomycete strains that produced ramoplanin-related compounds, and the analysis of the antimicrobial activity exhibited by these isolates. Our results strongly suggest the presence of new ramoplanin-analogs among these actinomycete producers.