Sun Jingyi, Kong Pan, Shi Jingru, Liu Yuan
Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China.
Joint International Research Laboratory of Agriculture and Agri-Product Safety, The Ministry of Education of China, Yangzhou University, Yangzhou 225009, China.
Pathogens. 2024 Sep 14;13(9):797. doi: 10.3390/pathogens13090797.
The accelerating spread of antibiotic resistance has significantly weakened the clinical efficacy of existing antibiotics, posing a severe threat to public health. There is an urgent need to develop novel antimicrobial alternatives that can bypass the mechanisms of antibiotic resistance and effectively kill multidrug-resistant (MDR) pathogens. Antimicrobial peptides (AMPs) are one of the most promising candidates to treat MDR pathogenic infections since they display broad-spectrum antimicrobial activities and are less prone to achieve drug resistance. In this study, we investigated the antibacterial capability and mechanisms of two machine learning-driven linear peptide compounds termed YI12 and FK13. We reveal that YI12 and FK13 exhibit broad-spectrum antibacterial properties against clinically significant bacterial pathogens, inducing no or minimal hemolysis in mammalian red blood cells. We further ascertain that YI12 and FK13 are resilient to heat and acid-base conditions, and exhibit susceptibility to hydrolytic enzymes and divalent cations under physiological conditions. Initial mechanistic investigations reveal that YI12 and FK13 compromise bacterial membrane integrity, leading to membrane potential dissipation and excessive reactive oxygen species (ROS) generation. Collectively, our findings highlight the prospective utility of these two cationic amphiphilic peptides as broad-spectrum antibacterial agents.
抗生素耐药性的加速传播显著削弱了现有抗生素的临床疗效，对公众健康构成了严重威胁。迫切需要开发新型抗菌替代品，以绕过抗生素耐药机制并有效杀灭多重耐药（MDR）病原体。抗菌肽（AMPs）是治疗MDR病原体感染最有前景的候选物之一，因为它们具有广谱抗菌活性且不易产生耐药性。在本研究中，我们研究了两种机器学习驱动的线性肽化合物YI12和FK13的抗菌能力及其作用机制。我们发现YI12和FK13对临床上重要的细菌病原体具有广谱抗菌特性，在哺乳动物红细胞中不诱导或仅诱导最小程度的溶血。我们进一步确定YI12和FK13对热和酸碱条件具有耐受性，并且在生理条件下对水解酶和二价阳离子敏感。初步的机制研究表明，YI12和FK13破坏细菌膜的完整性，导致膜电位耗散和过量活性氧（ROS）生成。总的来说，我们的研究结果突出了这两种阳离子两亲性肽作为广谱抗菌剂的潜在用途。
