Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, Queensland, Australia.
Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland, Australia.
Antimicrob Agents Chemother. 2018 Jan 25;62(2). doi: 10.1128/AAC.00986-17. Print 2018 Feb.
Resistance to antimicrobials is a growing problem in both developed and developing countries. In nations where AIDS is most prevalent, the human fungal pathogen 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 var. or showed an MIC of 1.56 to 3.13 μg/ml, while 20 clinical isolates of var. 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 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.
抗微生物药物耐药性是发达国家和发展中国家共同面临的一个日益严重的问题。在艾滋病流行最严重的国家，人类真菌病原体是导致死亡率的重要因素，其对现有抗真菌药物的耐药性不断增加，构成了日益扩大的威胁。我们研究了来自阳离子环状脂肽类抗菌药物的八肽素 C4，将其作为一种有潜力的新型抗真菌药物。八肽素 C4 对这种真菌病原体具有强大的选择性抑制作用，其 MIC 为 1.56μg/ml。进一步对八肽素 C4 针对 40 株临床分离株的 var. 或 进行的测试显示，MIC 为 1.56 至 3.13μg/ml，而 20 株临床分离株的 var. 则为 0.78 至 12.5μg/ml。在每种情况下，八肽素 C4 的 MIC 值与当前的抗真菌药物氟康唑和两性霉素 B 相当，甚至更好。 的负电荷多糖囊影响病原体对八肽素 C4 的敏感性，而黑色素化程度的影响则较小。对合成八肽素 C4 衍生物的测试提供了对结构-活性关系的深入了解，表明亲脂性氨基酸部分比阳离子二氨基丁酸基团对活性更为重要。八肽素具有开发为抗隐球菌治疗剂的巨大潜力。
