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

Kaixi Zhang,José R Mediavilla,Michelle E Turvey,Lin Ruan,Yabin Zhu,Kévin Pethe ,Oon Tek Ng,Sheethal Reghu,Xuewei Liu ,Barry N Kreiswirth,Kalisvar Marimuthu,Jinghua Ren,Yuguang Mu,Partha Pratim De,Damien Keogh,Paula T Hammond,Yonggui Robin ,Hongwei Duan,Subramanion L Jothy,Guillermo C Bazan,Zhangyong Si,Kam Chiu Tam ,Yang Liu,Yu Du,Cheerlavancha Raju,Mary B Chan‐Park

doi:10.1038/s41467-019-12702-8

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.

Highlights

The treatment of bacterial infections is hindered by the presence of biofilms and metabolically inactive persisters
We report a simple one-shot one-pot anionic ring openingpolymerization (AROP) strategy to synthesize a series of enantiomeric block co-beta-peptides, which cannot be made by sequential copolymerization
We showed that our copolymer is just as effective against HA-methicillin-resistant Staphylococcus aureus (MRSA) strains with resistance to multiple conventional antibiotics (Table 3, Fig. 5)

Summary

Introduction

The treatment of bacterial infections is hindered by the presence of biofilms and metabolically inactive persisters. The co-beta-peptide is bactericidal against methicillin-resistant Staphylococcus aureus (MRSA), including replicating, biofilm and persister bacterial cells, and disperses biofilm biomass. 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. Methicillin-resistant Staphylococcus aureus (MRSA), a WHO high-priority pathogen, is a leading cause of mortality due to antibiotic-resistant infections[9,10]. Alternative antibacterial agents should have bactericidal activity against replicating cells, persisters, and established biofilms. Cationic alpha-peptides and membrane-active agents have been investigated as alternative antimicrobials to combat biofilms and persisters[18,19], but unselective toxicity is a complicating factor[20]. Alpha-peptide antimicrobials are known to form facially amphiphilic (FA)

Methods

Results

Conclusion