Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, California, United States of America.
PLoS One. 2012;7(1):e29439. doi: 10.1371/journal.pone.0029439. Epub 2012 Jan 18.
We evaluated the in vitro activity of a merochlorin A, a novel compound with a unique carbon skeleton, against a spectrum of clinically relevant bacterial pathogens and against previously characterized clinical and laboratory Staphylococcus aureus isolates with resistance to numerous antibiotics.
Merochlorin A was isolated and purified from a marine-derived actinomycete strain CNH189. Susceptibility testing for merochlorin A was performed against previously characterized human pathogens using broth microdilution and agar dilution methods. Cytotoxicity was assayed in tissue culture assays at 24 and 72 hours against human HeLa and mouse sarcoma L929 cell lines.
The structure of as new antibiotic, merochlorin A, was assigned by comprehensive spectroscopic analysis. Merochlorin A demonstrated in vitro activity against Gram-positive bacteria, including Clostridium dificile, but not against Gram negative bacteria. In S. aureus, susceptibility was not affected by ribosomal mutations conferring linezolid resistance, mutations in dlt or mprF conferring resistance to daptomycin, accessory gene regulator knockout mutations, or the development of the vancomycin-intermediate resistant phenotype. Merochlorin A demonstrated rapid bactericidal activity against MRSA. Activity was lost in the presence of 20% serum.
The unique meroterpenoid, merochlorin A demonstrated excellent in vitro activity against S. aureus and C. dificile and did not show cross-resistance to contemporary antibiotics against Gram positive organisms. The activity was, however, markedly reduced in 20% human serum. Future directions for this compound may include evaluation for topical use, coating biomedical devices, or the pursuit of chemically modified derivatives of this compound that retain activity in the presence of serum.
我们评估了一种新型化合物——merochlorin A 的体外活性，该化合物具有独特的碳骨架，针对一系列临床相关的细菌病原体，以及以前表征的对多种抗生素具有耐药性的临床和实验室金黄色葡萄球菌分离株。
merochlorin A 从海洋来源的放线菌菌株 CNH189 中分离和纯化。使用肉汤微量稀释和琼脂稀释方法对以前表征的人类病原体进行 merochlorin A 的药敏试验。在 24 小时和 72 小时的组织培养测定中，用人类 HeLa 和小鼠肉瘤 L929 细胞系测定细胞毒性。
通过全面的光谱分析确定了一种新抗生素 merochlorin A 的结构。merochlorin A 对革兰氏阳性菌（包括艰难梭菌）表现出体外活性，但对革兰氏阴性菌没有活性。在金黄色葡萄球菌中，对核糖体突变赋予的利奈唑胺耐药性、对达托霉素耐药性的 dlt 或 mprF 突变、辅助基因调节剂缺失突变或万古霉素中介耐药表型的敏感性不受影响。merochlorin A 对耐甲氧西林金黄色葡萄球菌表现出快速杀菌活性。在存在 20%血清的情况下，活性丧失。
独特的 meroterpenoid merochlorin A 对金黄色葡萄球菌和艰难梭菌表现出极好的体外活性，并且与针对革兰氏阳性菌的当代抗生素没有交叉耐药性。然而，在 20%的人血清中活性显著降低。该化合物的未来方向可能包括评估局部使用、涂覆生物医学设备，或探索保留活性的该化合物的化学修饰衍生物在存在血清的情况下。
