Antimicrobial Octapeptin C4 Analogues Active against Cryptococcus Species.
Antimicrobial Octapeptin C4 Analogues Active against Cryptococcus Species.
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抗菌八肽C4类似物活跃于加密环球物种。
DOI：
10.1128/aac.00986-17
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发表时间：
2018-03
影响因子：
4.9
通讯作者：
Robertson AAB
中科院分区：
文献类型：
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作者：
Chitty JL;Butler MS;Suboh A;Edwards DJ;Cooper MA;Fraser JA;Robertson AAB
在发达国家和发展中国家，抗药性都是一个日益严重的问题。在艾滋病最流行的国家，人类真菌病原体新生隐球菌是导致死亡的一个重要因素，它对现有抗真菌药物日益增长的耐药性是一个日益扩大的威胁。我们研究了阳离子环脂肽类抗菌剂中的八肽C4，作为一种潜在的新的抗真菌药物。八肽C4是一种有效的、选择性的抑制该真菌病原体的药物，其MIC值为1.56MICg/ml。进一步对40株临床分离的新生葡萄球菌进行了八肽C4的检测。革兰氏阴性杆菌或新生杆菌的最低抑菌浓度为1.5 6~3.13μg/ml，而临床分离的2 0株新生葡萄球菌的最低抑菌浓度为1.5 6~3.13 pg/ml。Gattii的MIC值为0.78~12.5μg/ml，对八肽C4的MIC值与目前常用的抗真菌药物氟康唑和两性霉素B相当或更好。新生隐球菌带负电荷的多糖胶囊影响病原菌对八肽C4的敏感性，而黑化程度对其影响不大。测试合成的八肽C4衍生物提供了对结构活性关系的洞察，揭示了亲脂氨基酸部分对活性的影响比阳离子二氨基丁酸基团更重要。八肽类药物作为抗隐球菌类药物具有广阔的发展前景。
Resistance to antimicrobials is a growing problem in both developed and developing countries. In nations where AIDS is most prevalent, the human fungal pathogen Cryptococcus neoformans is a significant contributor to mortality, and its growing resistance to current antifungals is an ever-expanding threat. We investigated octapeptin C4, from the cationic cyclic lipopeptide class of antimicrobials, as a potential new antifungal. Octapeptin C4 was a potent, selective inhibitor of this fungal pathogen with an MIC of 1.56 μg/ml. Further testing of octapeptin C4 against 40 clinical isolates of C. neoformans var. grubii or neoformans showed an MIC of 1.56 to 3.13 μg/ml, while 20 clinical isolates of C. neoformans var. gattii had an MIC of 0.78 to 12.5 μg/ml. In each case, the MIC values for octapeptin C4 were equivalent to, or better than, current antifungal drugs fluconazole and amphotericin B. The negatively charged polysaccharide capsule of C. neoformans influences the pathogen's sensitivity to octapeptin C4, whereas the degree of melanization had little effect. Testing synthetic octapeptin C4 derivatives provided insight into the structure activity relationships, revealing that the lipophilic amino acid moieties are more important to the activity than the cationic diaminobutyric acid groups. Octapeptins have promising potential for development as anticryptococcal therapeutic agents.