Physical Sciences Division, Pacific Northwest National Laboratory, Richland, Washington 99352, United States.
Department of Chemistry, University of South Florida, Tampa, Florida 33620, United States.
ACS Nano. 2024 Aug 27;18(34):23077-23089. doi: 10.1021/acsnano.4c05250. Epub 2024 Aug 15.
Bacterial infections have been a serious threat to mankind throughout history. Natural antimicrobial peptides (AMPs) and their membrane disruption mechanism have generated immense interest in the design and development of synthetic mimetics that could overcome the intrinsic drawbacks of AMPs, such as their susceptibility to proteolytic degradation and low bioavailability. Herein, by exploiting the self-assembly and pore-forming capabilities of sequence-defined peptoids, we discovered a family of low-molecular weight peptoid antibiotics that exhibit excellent broad-spectrum activity and high selectivity toward a panel of clinically significant Gram-positive and Gram-negative bacterial strains, including vancomycin-resistant (VREF), methicillin-resistant (MRSA), methicillin-resistant (MRSE), , , and . Tuning the peptoid side chain chemistry and structure enabled us to tune the efficacy of antimicrobial activity. Mechanistic studies using transmission electron microscopy (TEM), bacterial membrane depolarization and lysis, and time-kill kinetics assays along with molecular dynamics simulations reveal that these peptoids kill both Gram-positive and Gram-negative bacteria through a membrane disruption mechanism. These robust and biocompatible peptoid-based antibiotics can provide a valuable tool for combating emerging drug resistance.
细菌感染一直是人类历史上的严重威胁。天然抗菌肽 (AMPs) 及其破坏细胞膜的机制激发了人们极大的兴趣，促使人们设计和开发合成模拟物，以克服 AMPs 的固有缺陷，例如易被蛋白水解降解和生物利用度低。在此，我们利用序列确定的肽的自组装和形成孔的能力，发现了一系列具有低分子量的肽类抗生素，它们对一系列临床上重要的革兰氏阳性和革兰氏阴性细菌菌株表现出优异的广谱活性和高选择性，包括耐万古霉素的 (VREF)、耐甲氧西林的 (MRSA)、耐甲氧西林的 (MRSE)、 、 、和 。通过调整肽的侧链化学和结构，我们能够调整抗菌活性的功效。使用透射电子显微镜 (TEM)、细菌膜去极化和裂解以及时效杀菌动力学测定以及分子动力学模拟的机制研究表明，这些肽通过破坏细胞膜的机制杀死革兰氏阳性和革兰氏阴性细菌。这些强大且具有生物相容性的基于肽的抗生素可以为对抗新出现的耐药性提供有价值的工具。
