摘要

      近年来发现的与细菌脂类II和脂类III结合的脱肽Teixobactin为新型抗菌药物的设计提供了一种有前途的分子支架。在此，我们描述了系统修饰的泰克霉素类似物的合成和抗菌评价。用脂肪族异甾体取代Ile11残基，在残基10处修饰胍基，并将一种刚性残基脱氢氨基酸引入大环中，生成了有用的结构活性信息。对一组临床相关的金黄色葡萄球菌和痤疮丙酸杆菌菌株进行广泛的抗菌药物敏感性评估，鉴定出新的先导化合物[Arg（Me）10，Nle11]泰克霉素，具有优异的杀菌活性（最低抑菌浓度（MIC）=2-4 μg mL-1）。值得注意的是，当与外膜破坏性抗生素colistin的亚MIC浓度结合时，几种teixobactin类似物对致病性革兰氏阴性铜绿假单胞菌的抗菌活性被“恢复”。一种[Tfn10，Nle11]泰克霉素（32 μg mL-1）-大肠杆菌素（2 μg mL-1；0.5×MIC）联合用药对铜绿假单胞菌PAO1的抗菌效果首次揭示了治疗革兰氏阴性感染的另一种治疗选择。

       Teixobactin, a recently discovered depsipeptide that binds to bacterial lipid II and lipid III, provides a promising molecular scaffold for the design of new antimicrobials. Herein, we describe the synthesis and antimicrobial evaluation of systematically modified teixobactin analogues. The replacement of the Ile¹¹ residue with aliphatic isosteres, the modification of the guanidino group at residue 10 and the introduction of a rigidifying residue, that is, dehydroamino acid, into the macrocyclic ring generated useful structure-activity information. Extensive antimicrobial susceptibility assessment against a panel of clinically relevant Staphylococcus aureus and Propionibacterium acnes strains led to the identification of the new lead compound, [Arg(Me)¹⁰ ,Nle¹¹ ]teixobactin, with an excellent bactericidal activity (minimum inhibitory concentration (MIC)=2-4 μg mL^-1 ). Significantly, the antimicrobial activity of several of the teixobactin analogues against the pathogenic Gram-negative Pseudomonas aeruginosa was "restored" when combined with the sub-MIC concentration of the outer membrane-disruptive antibiotic colistin. The antimicrobial effectiveness of a [Tfn¹⁰ ,Nle¹¹ ]teixobactin (32 μg mL^-1 )-colistin (2 μg mL^-1 ; 0.5×MIC) combination against P. aeruginosa PAO1 reveals, for the first time, an alternative therapeutic option in the treatment of Gram-negative infections.

        https://chemistry-europe.onlinelibrary.wiley.com/doi/abs/10.1002/chem.201801423