Genetically Engineered Lipopeptide Antibiotics Related to A54145 and Daptomycin with Improved Properties
Genetically Engineered Lipopeptide Antibiotics Related to A54145 and Daptomycin with Improved Properties
复制标题
DOI：
10.1128/aac.01307-09
复制
发表时间：
2010-01
影响因子：
4.9
通讯作者：
K. Nguyen;Xiaowei He;D. Alexander;Chen Li;J. Gu;Carmela T. M. Mascio;A. V. Van Praagh;L. Mortin;M. Chu;J. Silverman;P. Brian;R. H. Baltz
中科院分区：
文献类型：
--
作者：
K. Nguyen;Xiaowei He;D. Alexander;Chen Li;J. Gu;Carmela T. M. Mascio;A. V. Van Praagh;L. Mortin;M. Chu;J. Silverman;P. Brian;R. H. Baltz
达托霉素是一种环脂肽类抗生素，被批准用于治疗革兰氏阳性病原体引起的皮肤和皮肤结构感染以及金黄色葡萄球菌引起的菌血症和右心内膜炎。达托霉素不符合治疗社区获得性肺炎的非劣效性标准，可能是由于肺表面活性物质的隔离。许多类似物的达托霉素已产生的组合生物合成，但只有两个显示出改善的活性，在牛表面活性剂的存在下，都没有作为达托霉素在体外的活性。在本研究中，我们产生的杂合分子的结构相关的脂肽A54145在链霉菌fragrance和测试它们的抗菌活性存在下的牛表面活性剂。杂合A54145非核糖体肽合成酶（NRPS）的生物合成基因的构建通过基因工程和表达的lptI甲基转移酶基因，这是参与形成的3-甲基-谷氨酸（3 mGlu）残基在位置12的删除组合。部分化合物对S.金黄色葡萄球菌和其他革兰氏阳性病原体;一种化合物在牛表面活性剂存在下也具有高活性，具有低急性毒性，并在肺部感染的小鼠模型中显示出对肺炎链球菌的一些功效。
ABSTRACT Daptomycin is a cyclic lipopeptide antibiotic approved for the treatment of skin and skin structure infections caused by Gram-positive pathogens and for that of bacteremia and right-sided endocarditis caused by Staphylococcus aureus. Daptomycin failed to meet noninferiority criteria for the treatment of community-acquired pneumonia, likely due to sequestration in pulmonary surfactant. Many analogues of daptomycin have been generated by combinatorial biosynthesis, but only two displayed improved activity in the presence of bovine surfactant, and neither was as active as daptomycin in vitro. In the present study, we generated hybrid molecules of the structurally related lipopeptide A54145 in Streptomyces fradiae and tested them for antibacterial activity in the presence of bovine surfactant. Hybrid A54145 nonribosomal peptide synthetase (NRPS) biosynthetic genes were constructed by genetic engineering and were expressed in combination with a deletion of the lptI methyltransferase gene, which is involved in the formation of the 3-methyl-glutamic acid (3mGlu) residue at position 12. Some of the compounds were very active against S. aureus and other Gram-positive pathogens; one compound was also highly active in the presence of bovine surfactant, had low acute toxicity, and showed some efficacy against Streptococcus pneumoniae in a mouse model of pulmonary infection.