Qiu Ying Lau, Fui Mee Ng, Jin Wei Darryl Cheong, Yi Yong Alvin Yap, Yoke Yan Fion Tan, Roland Jureen, Jeffrey Hill, Cheng San Brian Chia, Discovery of an ultra-short linear antibacterial tetrapeptide with anti-MRSA activity from a structure–activity relationship study, European Journal of Medicinal Chemistry, Volume 105, 13 November 2015, Pages 138-144, ISSN 0223-5234, http://dx.doi.org/10.1016/j.ejmech.2015.10.015.
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 structureeactivity 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.