Prof. Yipeng Wang's group revealed the structural parameters and underlying mechanisms affecting the bacterial killing rate and drug-resistance development of antimicrobial peptides

Infections caused by drug-resistant pathogens have become a severe challenge for public health, which represent the third most common cause of human death worldwide. Novel therapeutic strategies are pressingly required to cope with the drug-resistance threat. Antimicrobial peptides (AMPs) are a class of small peptides with direct microbial killing ability, which are regarded as having great potential in the treatment of drug-resistant bacterial infections. To date, more than 30 AMPs-related drugs are in clinical trials. Rapid antimicrobial action is an important advantage of antimicrobial peptides (AMPs) over antibiotics, which is also a reason for AMPs being less likely to induce bacterial resistance. However, the structural parameters and underlying mechanisms affecting the bacterial killing rate of AMPs remain unknown.

In recent years, Prof. Yipeng Wang's group from the College of Pharmaceutical Sciences, Soochow University has carried out a series of studies on the identification, structural modification, and application of AMPs (Med Res Rev. 2022, 42(4):1377-1422;ACS Infect Dis. 2020, 6:2451-2467;J Med Chem. 2018, 61(15):6846-6857;J Med Chem. 2018, 61(5):2075-2086;J Bio Chem. 2017, 474(16):2861-2885;J Biol Chem. 2015, 290(27):16633-16652). On the basis of the above work, the team recently cooperated with collaborators from the Beijing Normal University and the Dalian University of Technology to reveal that hydrophobicity, rather than other structure parameters, is the critical structural parameter determining the bacterial killing rate of α-helical AMPs. With the hydrophobicity increase, the action rates of AMPs including bacterial binding, lipopolysaccharides neutralization, and outer and inner membrane permeabilization increased. Additionally, the higher hydrophobic AMPs with enhanced bacterial killing rates possess better in vivo therapeutic potency and a lower propensity to induce bacterial resistance. These findings revealed the importance of the bacterial killing rate for AMPs and are of great significance to the design and optimization of AMP-related drugs.

Figure 1. Schematic diagram of the mechanism by which hydrophobicity determines the bacterial killing rate and drug-resistance of α-helical AMPs

This work was supported by funding from the National Natural Science Foundation of China, the Key Research & Development Plan in Social Development of Jiangsu Province, and the Priority Academic Program Development of the Jiangsu Higher Education Institutes (PAPD). The first authors are Minghui Zhang and Jianhong Ouyang from Soochow university, and Lei Fu from Beijing Normal University. The corresponding authors are Prof. Yipeng Wang from Soochow University, Prof. Lianghui Gao from Beijing Normal University, and Prof. Haining Yu from the Dalian University of Technology. This work is also assisted by Prof. Bing Yuan from the Songshan Lake Materials Laboratory, Prof. Kai Yang from the Center for Soft Condensed Matter Physics and Interdisciplinary Research & School of Physical Science and Technology, Soochow University, and Prof. Hengte Ke from the College of Pharmaceutical Sciences, Soochow University.

References:

Zhang M^＃, Ouyang J^＃, Fu L^＃, Xu C, Ge Y, Sun S, Li X, Lai S, Ke H, Yuan B, Yang K, Yu H*, Gao L*, Wang Y*. Hydrophobicity determines the bacterial killing rate of α-helical antimicrobial peptides and influences the bacterial resistance development. J Med Chem. 2022 Oct 25. doi: 10.1021/acs.jmedchem.2c01238.