Enantiomeric glycosylated cationic block co-beta-peptides eradicate Staphylococcus aureus biofilms and antibiotic-tolerant persisters

• Published in: Nature communications Vol. 10; no. 1; pp. 4792 - 14
• Main Authors: Zhang, Kaixi, Du, Yu, Si, Zhangyong, Liu, Yang, Turvey, Michelle E., Raju, Cheerlavancha, Keogh, Damien, Ruan, Lin, Jothy, Subramanion L., Reghu, Sheethal, Marimuthu, Kalisvar, De, Partha Pratim, Ng, Oon Tek, Mediavilla, José R., Kreiswirth, Barry N., Chi, Yonggui Robin, Ren, Jinghua, Tam, Kam C., Liu, Xue-Wei, Duan, Hongwei, Zhu, Yabin, Mu, Yuguang, Hammond, Paula T., Bazan, Guillermo C., Pethe, Kevin, Chan-Park, Mary B.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.10.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 14/19; 140/131; 140/58; 147/135; 147/143; 3T3 Cells; 45/22; 45/77; 631/326/22; 631/326/41; 631/326/421; 639/638/455; 64; 64/60; Animals; Antibacterial activity; Antibiotics; Bacteria; Bacterial diseases; Bacterial infections; beta-Lactams - chemical synthesis; beta-Lactams - pharmacology; beta-Lactams - therapeutic use; Biocompatibility; Biofilms; Biofilms - drug effects; Daptomycin; Drug resistance; Drug Resistance, Multiple, Bacterial; Glucose; Glucose - chemical synthesis; Glucose - pharmacology; Glucose - therapeutic use; Humanities and Social Sciences; Humans; In Vitro Techniques; Infections; Lysine; Lysine - analogs & derivatives; Lysine - chemical synthesis; Lysine - pharmacology; Lysine - therapeutic use; Methicillin; Methicillin-Resistant Staphylococcus aureus - drug effects; Mice; Microbial Sensitivity Tests; multidisciplinary; Peptides; Polymerization; Replication; Ring opening polymerization; Science; Science (multidisciplinary); Staphylococcal Skin Infections - drug therapy; Staphylococcus aureus; Staphylococcus infections; Toxicity; Vancomycin
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-12702-8

The treatment of bacterial infections is hindered by the presence of biofilms and metabolically inactive persisters. Here, we report the synthesis of an enantiomeric block co-beta-peptide, poly(amido-D-glucose)- block -poly(beta-L-lysine), with high yield and purity by one-shot one-pot anionic-ring opening (co)polymerization. The co-beta-peptide is bactericidal against methicillin-resistant Staphylococcus aureus (MRSA), including replicating, biofilm and persister bacterial cells, and also disperses biofilm biomass. It is active towards community-acquired and hospital-associated MRSA strains which are resistant to multiple drugs including vancomycin and daptomycin. Its antibacterial activity is superior to that of vancomycin in MRSA mouse and human ex vivo skin infection models, with no acute in vivo toxicity in repeated dosing in mice at above therapeutic levels. The copolymer displays bacteria-activated surfactant-like properties, resulting from contact with the bacterial envelope. Our results indicate that this class of non-toxic molecule, effective against different bacterial sub-populations, has promising potential for the treatment of S. aureus infections. The authors report the synthesis of an enantiomeric block co-beta-peptide that kills methicillin-resistant Staphylococcus aureus , including biofilm and persister bacterial cells, and disperses biofilms. The copolymer displays antibacterial activity in human ex vivo and mouse in vivo infection models without toxicity.