Department of Bioengineering, School of Medicine & School of Engineering, Stanford University, Stanford, California 94305, United States.
Department of Otolaryngology, Head and Neck Surgery, School of Medicine, Stanford University, Stanford, California 94305, United States.
ACS Infect Dis. 2022 Sep 9;8(9):1823-1830. doi: 10.1021/acsinfecdis.2c00288. Epub 2022 Aug 26.
Although persister cells are the root cause of resistance development and relapse of chronic infections, more attention has been focused on developing antimicrobial agents against resistant bacterial strains than on developing anti-persister agents. Frustratingly, the global preclinical antibacterial pipeline does not include any anti-persister drug. Therefore, the central point of this work is to explore antimicrobial peptidomimetics called peptoids (sequence-specific oligo--substituted glycines) as a new class of anti-persister drugs. In this study, we demonstrate that one particular antimicrobial peptoid, the sequence-specific pentamer TM5, is active against planktonic persister cells and sterilizes biofilms formed by both Gram-negative and Gram-positive bacteria. Moreover, we demonstrate the potential of TM5 to inhibit cytokine production induced by lipopolysaccharides from Gram-negative bacteria. We anticipate that this work can pave the way to the development of new anti-persister agents based on antimicrobial peptoids of this class to simultaneously help address the crisis of bacterial resistance and reduce the occurrence of the relapse of chronic infections.
尽管持留细胞是导致慢性感染耐药性发展和复发的根本原因，但人们更多地关注开发针对耐药菌株的抗菌药物，而不是开发抗持留药物。令人沮丧的是，全球抗菌药物临床前管道中没有任何抗持留药物。因此，这项工作的重点是探索称为肽拟似物（序列特异性寡取代甘氨酸）的抗菌肽作为一类新的抗持留药物。在这项研究中，我们证明了一种特定的抗菌肽拟似物，即序列特异性五聚体 TM5，对浮游持留细胞具有活性，并能杀菌革兰氏阴性菌和革兰氏阳性菌形成的生物膜。此外，我们证明了 TM5 抑制革兰氏阴性菌脂多糖诱导细胞因子产生的潜力。我们预计这项工作将为开发基于此类抗菌肽拟似物的新型抗持留药物铺平道路，从而有助于解决细菌耐药性危机，并减少慢性感染复发的发生。
