Carmody Maria, Murphy Barry, Byrne Barry, Power Patrick, Rai Dilip, Rawlings Bernard, Caffrey Patrick
Department of Industrial Microbiology, Centre for Synthesis and Chemical Biology, Conway Institute for Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.
J Biol Chem. 2005 Oct 14;280(41):34420-6. doi: 10.1074/jbc.M506689200. Epub 2005 Aug 3.
Amphotericin B is a medically important antifungal antibiotic that is also active against human immunodeficiency virus, Leishmania parasites, and prion diseases. The therapeutic use of amphotericin B is restricted by severe side effects that can be moderated by liposomal formulation or structural alteration. Chemical modification has shown that suppression of charge on the exocyclic carboxyl group of amphotericin B substantially reduces toxicity. We report targeted deletions of the amphN cytochrome P450 gene from the chromosome of the amphotericin-producing bacterium Streptomyces nodosus. The mutant strains produced amphotericin analogues in which methyl groups replace the exocyclic carboxyl groups. These compounds retained antifungal activity and had reduced hemolytic activity.
两性霉素B是一种具有重要医学意义的抗真菌抗生素，对人类免疫缺陷病毒、利什曼原虫和朊病毒疾病也有活性。两性霉素B的治疗应用受到严重副作用的限制，而脂质体制剂或结构改变可减轻这些副作用。化学修饰表明，抑制两性霉素B外环羧基上的电荷可大幅降低毒性。我们报告了从产生两性霉素的细菌诺卡氏链霉菌染色体中靶向缺失amphN细胞色素P450基因。突变菌株产生的两性霉素类似物中，甲基取代了外环羧基。这些化合物保留了抗真菌活性，且溶血活性降低。
