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

Kaixi Zhang, Yu Du, Zhangyong Si, Yang Liu, Michelle E. Turvey, Cheerlavancha Raju, Damien Keogh, Lin Ruan, Subramanion L. Jothy, Sheethal Reghu, Kalisvar Marimuthu, Partha Pratim De, Oon Tek Ng, José R. Mediavilla, Barry N. Kreiswirth, Yonggui Robin Chi, Jinghua Ren, Kam C. Tam, Xue-Wei Liu, Hongwei Duan, Yabin Zhu, Yuguang Mu, Paula T. Hammond, Guillermo C. Bazan, Kevin Pethe () and Mary B. Chan-Park ()
Additional contact information
Kaixi Zhang: Nanyang Technological University
Yu Du: Nanyang Technological University
Zhangyong Si: Nanyang Technological University
Yang Liu: Nanyang Technological University
Michelle E. Turvey: Singapore-MIT Alliance for Research & Technology Centre
Cheerlavancha Raju: Nanyang Technological University
Damien Keogh: Nanyang Technological University
Lin Ruan: Nanyang Technological University
Subramanion L. Jothy: Nanyang Technological University
Sheethal Reghu: Nanyang Technological University
Kalisvar Marimuthu: Tan Tock Seng Hospital
Partha Pratim De: Tan Tock Seng Hospital
Oon Tek Ng: Tan Tock Seng Hospital
José R. Mediavilla: Hackensack Meridian Health
Barry N. Kreiswirth: Hackensack Meridian Health
Yonggui Robin Chi: Nanyang Technological University
Jinghua Ren: Huazhong University of Science & Technology
Kam C. Tam: University of Waterloo
Xue-Wei Liu: Nanyang Technological University
Hongwei Duan: Nanyang Technological University
Yabin Zhu: Medical School of Ningbo University, Ningbo
Yuguang Mu: Nanyang Technological University
Paula T. Hammond: Massachusetts Institute of Technology
Guillermo C. Bazan: University of California Santa Barbara
Kevin Pethe: Nanyang Technological University
Mary B. Chan-Park: Nanyang Technological University

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-12702-8

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