Discovery of an ultra-short linear antibacterial tetrapeptide with anti-MRSA activity from a structure-activity relationship study.
The overuse and misuse of antibiotics has resulted in the emergence of drug-resistant pathogenic bacteria, including meticillin-resistant Staphylococcus aureus (MRSA), the primary pathogen responsible for human skin and soft-tissue infections. Antibacterial peptides are known to kill bacteria by rapidly disrupting their membranes and are deemed plausible alternatives to conventional antibiotics. One advantage of their membrane-targeting mode of action is that bacteria are unlikely to develop resistance as changing their cell membrane structure and morphology would likely involve extensive genetic mutations. However, major concerns in using peptides as antibacterial drugs include their instability towards plasma proteases, toxicity towards human cells due to their membrane-targeting mode of action and high manufacturing cost. These concerns can be mitigated by developing peptides as topical agents, by the judicial selection of amino acids and developing very short peptides respectively. In this preliminary report, we reveal a linear, non-hemolytic tetrapeptide with rapid bactericidal activity against MRSA developed from a structure-activity relationship study based on the antimicrobial hexapeptide WRWRWR-NH2. Our finding opens promising avenues for the development of ultra-short antibacterials to treat multidrug-resistant MRSA skin and soft tissue infections.
Experimental Therapeutics Centre, Agency for Science, Technology and Research (A*STAR), 31 Biopolis Way, Nanos #03-01 138669, Singapore.
Qiu Ying
QY
Lau
Experimental Therapeutics Centre, Agency for Science, Technology and Research (A*STAR), 31 Biopolis Way, Nanos #03-01 138669, Singapore.
Fui Mee
FM
Ng
Experimental Therapeutics Centre, Agency for Science, Technology and Research (A*STAR), 31 Biopolis Way, Nanos #03-01 138669, Singapore.
Jin Wei Darryl
JW
Cheong
Experimental Therapeutics Centre, Agency for Science, Technology and Research (A*STAR), 31 Biopolis Way, Nanos #03-01 138669, Singapore.
Yi Yong Alvin
YY
Yap
Experimental Therapeutics Centre, Agency for Science, Technology and Research (A*STAR), 31 Biopolis Way, Nanos #03-01 138669, Singapore.
Yoke Yan Fion
YY
Tan
Department of Laboratory Medicine, National University Hospital, 5 Lower Kent Ridge Road 119074, Singapore.
Roland
R
Jureen
Experimental Therapeutics Centre, Agency for Science, Technology and Research (A*STAR), 31 Biopolis Way, Nanos #03-01 138669, Singapore.
Jeffrey
J
Hill
Experimental Therapeutics Centre, Agency for Science, Technology and Research (A*STAR), 31 Biopolis Way, Nanos #03-01 138669, Singapore. Electronic address: cschia@etc.a-star.edu.sg.
Cheng San Brian
CS
Chia
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008968:Molecular Conformation; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D009842:Oligopeptides
Antibacterial peptide; Antimicrobial peptide; MRSA; SSTI; Skin infection