Department of Chemistry, University of Waterloo, 200 University Avenue West, Waterloo, Ontario N2L 3G1, Canada.
ACS Infect Dis. 2022 Oct 14;8(10):2073-2083. doi: 10.1021/acsinfecdis.2c00157. Epub 2022 Sep 9.
Paenibacterin A1 (PA1) is a broad-spectrum, cationic cyclic lipodepsipeptide antibiotic isolated from . In this study, the roles of the cationic residues and lipid tail length on the in vitro antibacterial and hemolytic activities of PA1 was examined in the context of an active PA1 analogue, called PAK, in which the two D-Orn residues in PA1 were converted to D-Lys residues. The effect of reducing the length of the lipid tail in PAK from 15 to 12-10 carbons on the minimum inhibitory concentration (MIC) depended upon the bacteria. This change had little effect on the MIC against and but resulted in a reduction in activity against most of the ESKAPE pathogens tested with the exception of . Any one of the four cationic residues in PAK could be replaced with alanine with only a minimal effect on its MIC against , , , , and MSSA. For and the two MRSA strains tested, the presence of cationic residues at positions 7 and 12 are not important for activity, while the cationic residues at positions 1 and 4 are important. While PAK exhibited some hemolysis at 8 μg/mL and 70% hemolysis at 128 μg/mL, its C-12 and C-10 analogues were not hemolytic up to 128 μg/mL. All PAK analogues that had one or two cationic residues replaced with alanine were as hemolytic as or more hemolytic than PAK.
Paenibacterin A1 (PA1) 是一种广谱、阳离子环脂肽抗生素，从 中分离得到。在这项研究中，研究了阳离子残基和脂质尾长度在 PA1 类似物（称为 PAK）体外抗菌和溶血活性中的作用，在 PA1 中，两个 D-Orn 残基被转化为 D-Lys 残基。在 PAK 中，将脂质尾的长度从 15 个减少到 12-10 个碳原子，对最小抑菌浓度（MIC）的影响取决于细菌。这种变化对 MIC 几乎没有影响，对 和 ，但除 外，对大多数测试的 ESKAPE 病原体的活性降低。PAK 中的四个阳离子残基中的任何一个都可以用丙氨酸替换，对其 MIC 对 、 、 、和 MSSA 的影响最小。对于 和测试的两种 MRSA 菌株，位置 7 和 12 的阳离子残基的存在对活性不重要，而位置 1 和 4 的阳离子残基很重要。虽然 PAK 在 8 μg/mL 时表现出一定的溶血，在 70%溶血在 128 μg/mL 时，其 C-12 和 C-10 类似物在 128 μg/mL 时没有溶血。所有一个或两个阳离子残基被丙氨酸取代的 PAK 类似物的溶血程度与 PAK 相同或更高。
