Handley Thomas N G, Li Wenyi, Welch Nicholas G, O'Brien-Simpson Neil M, Hossain Mohammed Akhter, Wade John D
The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.
School of Chemistry, University of Melbourne, Parkville, VIC, Australia.
Front Chem. 2022 Apr 13;10:875233. doi: 10.3389/fchem.2022.875233. eCollection 2022.
The day is rapidly approaching where current antibiotic therapies will no longer be effective due to the development of multi-drug resistant bacteria. Antimicrobial peptides (AMPs) are a promising class of therapeutic agents which have the potential to help address this burgeoning problem. Proline-rich AMPs (PrAMPs) are a sub-class of AMPs, that have multiple modes of action including modulation of the bacterial protein folding chaperone, DnaK. They are highly effective against Gram-negative bacteria and have low toxicity to mammalian cells. Previously we used an approach to identify new potential PrAMPs from the DRAMP database. Four of these peptides, antibacterial napin, attacin-C, P9, and PP30, were each chemically assembled and characterized. Together with synthetic oncocin as a reference, each peptide was then assessed for antibacterial activity against Gram-negative/Gram-positive bacteria and for DnaK modulation activity. We observed that these peptides directly modulate DnaK activity independently of eliciting or otherwise an antibiotic effect. Based on our findings, we propose a change to our previously established PrAMP definition to remove the requirement for antimicrobial activity in isolation, leaving the following classifiers: >25% proline, modulation of DnaK AND/OR the 70S ribosome, net charge of +1 or more, produced in response to bacterial infection AND/OR with pronounced antimicrobial activity.
由于多重耐药细菌的出现，当前的抗生素疗法将不再有效的日子正在迅速临近。抗菌肽（AMPs）是一类很有前景的治疗剂，有潜力帮助解决这个迅速发展的问题。富含脯氨酸的抗菌肽（PrAMPs）是抗菌肽的一个亚类，具有多种作用模式，包括对细菌蛋白折叠伴侣DnaK的调节作用。它们对革兰氏阴性菌非常有效，对哺乳动物细胞毒性低。之前我们采用一种方法从DRAMP数据库中鉴定新的潜在PrAMPs。其中四种肽，抗菌蛋白napin、attacin-C、P9和PP30，分别进行了化学合成和表征。然后，以合成的癌基因蛋白作为参考，评估每种肽对革兰氏阴性/革兰氏阳性菌的抗菌活性以及对DnaK的调节活性。我们观察到这些肽直接调节DnaK活性，而与是否引发抗生素效应无关。基于我们的发现，我们提议对我们之前确定的PrAMP定义进行修改，去除对抗菌活性单独存在的要求，留下以下分类标准：脯氨酸含量>25%，对DnaK和/或70S核糖体有调节作用，净电荷为+1或更高，响应细菌感染产生和/或具有显著的抗菌活性。
