Bédard François, Fliss Ismail, Biron Eric
Faculty of Pharmacy and Institute of Nutrition and Functional Foods , Université Laval , Québec , Québec G1V 0A6 , Canada.
Laboratory of Medicinal Chemistry , CHU de Québec Research Centre , 2705 Boulevard Laurier , Québec , Québec G1V 4G2 , Canada.
ACS Infect Dis. 2019 Feb 8;5(2):199-207. doi: 10.1021/acsinfecdis.8b00204. Epub 2018 Dec 24.
The antimicrobial peptide bactofencin A is an unmodified non-pediocin-like bacteriocin that inhibits several clinically relevant pathogens, including Listeria monocytogenes and Staphylococcus aureus. Here we report the synthesis and structure-activity relationship studies of bactofencin A and novel analogues thereof. Synthetic bactofencin A was a potent inhibitor of L. monocytogenes (MIC = 8.0 μM) and S. aureus (MIC = 4.0 μM), similar to the bacteriocin produced naturally by Lactobacillus salivarius. Of particular interest is the fact that linear analogues lacking the disulfide bond found in bactofencin A were as potent and also active against several strains of methicillin-resistant S. aureus (MRSA) and one strain of vancomycin-resistant S. aureus (VRSA). Supported by the structure-activity relationship study, investigation of the interaction of bactofencin A with bacterial membrane by molecular dynamics simulations showed the importance of the positively charged N-terminal tail for peptide-membrane interaction. These results suggest that the C-terminal macrocycle is involved in target protein binding and bacterial growth inhibition.
抗菌肽杆菌防御素A是一种未修饰的非类片球菌素样细菌素，可抑制多种临床相关病原体，包括单核细胞增生李斯特菌和金黄色葡萄球菌。在此，我们报告了杆菌防御素A及其新型类似物的合成和构效关系研究。合成的杆菌防御素A是单核细胞增生李斯特菌（MIC = 8.0 μM）和金黄色葡萄球菌（MIC = 4.0 μM）的有效抑制剂，类似于唾液乳杆菌天然产生的细菌素。特别值得关注的是，缺乏杆菌防御素A中发现的二硫键的线性类似物同样有效，并且对几种耐甲氧西林金黄色葡萄球菌（MRSA）菌株和一株耐万古霉素金黄色葡萄球菌（VRSA）也有活性。在构效关系研究的支持下，通过分子动力学模拟研究杆菌防御素A与细菌膜的相互作用表明，带正电荷的N末端尾巴对于肽与膜的相互作用很重要。这些结果表明，C末端大环参与靶蛋白结合和细菌生长抑制。
