Dewangan Rikeshwer Prasad, Verma Devesh Pratap, Verma Neeraj Kumar, Gupta Ankit, Pant Garima, Mitra Kalyan, Habib Saman, Ghosh Jimut Kanti
Biochemistry and Structural Biology Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, Uttar Pradesh 226031, India.
Electron Microscopy Unit, SAIF Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
J Med Chem. 2022 Apr 14;65(7):5433-5448. doi: 10.1021/acs.jmedchem.1c01809. Epub 2022 Mar 17.
Toward the design of new proline-rich peptidomimetics, a short peptide segment, present in several proline-rich antimicrobial peptides (AMPs), was selected. Fatty acids of varying lengths and spermine were conjugated at the N- and C-terminals of the peptide, respectively. Spermine-conjugated lipopeptides, C-PR-Spn and C-PR-Spn, exhibited minimum inhibitory concentrations within 1.5-6.2 μM against the tested pathogens including resistant bacteria and insignificant hemolytic activity against human red blood cells up to 100 μM concentrations and demonstrated resistance against trypsin digestion. C-PR-Spn and C-PR-Spn showed synergistic antimicrobial activity against multidrug-resistant methicillin-resistant with several tested antibiotics. These lipopeptides did not permeabilize bacterial membrane-mimetic lipid vesicles or damage the membrane like the nonmembrane-lytic AMP, buforin-II. The results suggested that C-PR-Spn and C-PR-Spn could interact with the 70S ribosome of and inhibit its protein synthesis. C-PR-Spn and C-PR-Spn demonstrated superior clearance of bacteria from the spleen, liver, and kidneys of mice, infected with ATCC 25923 compared to levofloxacin.
为了设计新的富含脯氨酸的肽模拟物，我们选择了存在于几种富含脯氨酸的抗菌肽（AMPs）中的一个短肽片段。分别在该肽的N端和C端连接了不同长度的脂肪酸和精胺。精胺共轭脂肽C-PR-Spn和C-PR-Spn对包括耐药菌在内的受试病原体表现出1.5 - 6.2 μM的最低抑菌浓度，在高达100 μM的浓度下对人红细胞的溶血活性不显著，并对胰蛋白酶消化具有抗性。C-PR-Spn和C-PR-Spn与几种受试抗生素对多重耐药的耐甲氧西林金黄色葡萄球菌表现出协同抗菌活性。这些脂肽不像非膜裂解型抗菌肽蟾蜍灵 - II那样使细菌膜模拟脂质体通透或破坏膜。结果表明，C-PR-Spn和C-PR-Spn可能与金黄色葡萄球菌的70S核糖体相互作用并抑制其蛋白质合成。与左氧氟沙星相比，C-PR-Spn和C-PR-Spn在感染金黄色葡萄球菌ATCC 25923的小鼠脾脏、肝脏和肾脏中显示出更好的细菌清除效果。
