2. Academic Validation
  3. Development of Antibacterial Peptides with Membrane Disruption and Folate Pathway Inhibitory Activities against Methicillin-Resistant Staphylococcus aureus

Development of Antibacterial Peptides with Membrane Disruption and Folate Pathway Inhibitory Activities against Methicillin-Resistant Staphylococcus aureus

  • J Med Chem. 2024 Jan 25;67(2):1044-1060. doi: 10.1021/acs.jmedchem.3c01360.
Chunlei Li 1 2,  Ziyi Zhou 3,  Weitao Wang 1,  Yanqiu Zhao 1,  Xin Yin 1,  Yiwei Meng 1,  Peipei Zhao 1,  Mengmeng Wang 1,  Xueting Liu 4,  Xinye Wang 4,  Shenlin Wang 4,  Biao Ren 3,  Lixin Zhang 4,  Xuekui Xia 1
Affiliations

Affiliations

  • 1 Shandong Provincial Key Laboratory for Bio-Manufacturing, Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250103, China.
  • 2 Department of Pharmacy, Qilu Hospital, Cheloo College of Medicine, Shandong University, Jinan 250012, China.
  • 3 State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu 610041, China.
  • 4 State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China.
PMID: 38173250 DOI: 10.1021/acs.jmedchem.3c01360
Abstract

Antimicrobial peptides (AMPs) offer an opportunity to overcome multidrug resistance. Here, novel peptides were designed based on AMP fragments derived from sea cucumber hemolytic lectin to enhance anti-methicillin-resistant Staphylococcus aureus (MRSA) activity with less side effects. Two designed peptides, CGS19 (LARVARRVIRFIRRAW-NH2) and CGS20 (RRRLARRLIFFIRRAW-NH2), exhibited strong Antibacterial activities against clinically isolated MRSA with MICs of 3-6 μM, but no obvious cytotoxicity was observed. Consistently, CGS19 and CGS20 exerted rapid bactericidal activity and effectively induced 5.9 and 5.8 log reduction of MRSA counts in mouse subeschar, respectively. Further, CGS19 and CGS20 kill bacteria not only through disturbing membrane integrity but also by binding formate-tetrahydrofolate Ligase, a key enzyme in the folate metabolism pathway, thereby inhibiting the folate pathway of MRSA. CGS19 and CGS20 are promising lead candidates for drug development against MRSA Infection. The dual mechanisms on the identical peptide sequence or scaffold might be an underappreciated manner of treating life-threatening pathogens.

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