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ACS Med Chem Lett. 2017 Sep 20;8(10):1083-1088. doi: 10.1021/acsmedchemlett.7b00285. eCollection 2017.

Targeting Wall Teichoic Acid in Situ with Branched Polyethylenimine Potentiates β-Lactam Efficacy against MRSA.

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  • 1Department of Chemistry and Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, 101 Stephenson Parkway, Norman, Oklahoma 73019, United States.

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) is a medical concern. Here, we show that branched polyethylenimine (BPEI), a nontoxic, cationic polymer, restores MRSA's susceptibility to β-lactam antibiotics. Checkerboard assays with MRSA demonstrated synergy between BPEI and β-lactam antibiotics. A time-killing curve showed BPEI to be bactericidal in combination with oxacillin. BPEI did not potentiate efficacy with vancomycin, chloramphenicol, or linezolid. When exposed to BPEI, MRSA increased in size and had difficulty forming septa. BPEI electrostatically binds to wall teichoic acid (WTA), a cell wall anionic polymer of Gram-positive bacteria that is important for localization of certain cell wall proteins. Lack of potentiation in a WTA knockout mutant supports the WTA-based mechanism. These data suggest that BPEI may prevent proper localization of cell wall machinery by binding to WTA; leading to cell death when administered in combination with β-lactam antibiotics. Negligible in vitro toxicity suggests the combination could be a viable treatment option.

KEYWORDS:

Branched polyethylenimine; MRSA; antibiotic resistance; bacteria; wall teichoic acid; β-lactams

PMID:
29057055
PMCID:
PMC5641947
[Available on 2018-10-12]
DOI:
10.1021/acsmedchemlett.7b00285
[PubMed]
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