Using Diphenylphosphoryl Azide (DPPA) for the Facile Synthesis of Biodegradable Antiseptic Random Copolypeptides.
A facile method has been developed for the large-scale synthesis of random copolypeptides composed of multiple (i.e., cationic, hydrophobic, and hydrophilic) amino acids and their relative ratios have been optimized for broad-spectrum antibacterial effect. The copolypeptides obtained have measured compositions close to the design ratios in spite of the differing reactivities of the different amino acids. An optimized random copolypeptide of lysine, leucine, and serine (denoted as KLS-3) mimicking the composition of LL-37 host defense peptide gives broad spectrum antibacterial activity against clinically relevant Gram-negative and Gram-positive bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa (PAO1) with minimum inhibitory concentrations (MICs) of 32-64 μg mL-1, as well as good MICs against multidrug resistant Gram-negative bacteria of Escherichia coli EC 958 (64 μg mL-1) and Klebseilla pneumoniae PTR3 (128 μg mL-1). This method can be applied to the facile large-scale copolymerization of multiple amino acids, including unnatural amino acids, to make effective antibacterial copolypeptides.
School of Chemical and Biomedical Engineering, and Centre for Antimicrobial Bioengineering, Nanyang Technological University, 62 Nanyang Drive, Singapore, 637459, Singapore.
Yuji
Y
Pu
School of Chemical and Biomedical Engineering, and Centre for Antimicrobial Bioengineering, Nanyang Technological University, 62 Nanyang Drive, Singapore, 637459, Singapore.
Yu
Y
Du
School of Chemical and Biomedical Engineering, and Centre for Antimicrobial Bioengineering, Nanyang Technological University, 62 Nanyang Drive, Singapore, 637459, Singapore.
Mya Mya
MM
Khin
The Singapore Centre for Environmental Life Sciences Engineering, Nanyang Technological University, Singapore, 637551, Singapore.
Vikashini
V
Ravikumar
The Singapore Centre for Environmental Life Sciences Engineering and School of Biological Sciences, Nanyang Technological University, Singapore, 637551, Singapore.
Scott A
SA
Rice
School of Chemical and Biomedical Engineering, and Centre for Antimicrobial Bioengineering, Nanyang Technological University, 62 Nanyang Drive, Singapore, 637459, Singapore.
Hongwei
H
Duan
School of Chemical and Biomedical Engineering, and Centre for Antimicrobial Bioengineering, Nanyang Technological University, 62 Nanyang Drive, Singapore, 637459, Singapore.
Mary B
MB
Chan-Park
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D001386:Azides / Q000737:chemistry* / Q000494:pharmacology; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D058105:Polymerization; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D001386:Azides; C007523:diphenylphosphorazidate
antibacterial peptides; broad-spectrum antibacterial activity; diphenylphosphoryl azide; peptide synthesis