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J Antibiot (Tokyo). 2016 Dec;69(12):871-878. doi: 10.1038/ja.2016.44. Epub 2016 May 18.

Efficacy of ampicillin against methicillin-resistant Staphylococcus aureus restored through synergy with branched poly(ethylenimine).

Author information

1
Department of Chemistry and Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, Norman, OK, USA.
2
Samuel Roberts Noble Microscopy Laboratory, University of Oklahoma, Norman, OK, USA.

Abstract

β-Lactam antibiotics kill Staphylococcus aureus bacteria by inhibiting the function of cell wall penicillin-binding proteins (PBPs) 1 and 3. However, β-lactams are ineffective against PBP2a, used by methicillin-resistant S. aureus (MRSA) to perform essential cell wall crosslinking functions. PBP2a requires teichoic acid to properly locate and orient the enzyme, and thus MRSA is susceptible to antibiotics that prevent teichoic acid synthesis in the bacterial cytoplasm. As an alternative, we have used branched poly(ethylenimine), BPEI, to target teichoic acid in the bacterial cell wall. The result is restoration of MRSA susceptibility to the β-lactam antibiotic ampicillin with a MIC of 1 μg ml-1, superior to that of vancomycin (MIC=3.7 μg ml-1). A checkerboard assay shows synergy of BPEI and ampicillin. NMR data show that BPEI alters the teichoic acid chemical environment. Laser scanning confocal microscopy images show BPEI residing on the bacterial cell wall, where teichoic acids and PBPs are located.

PMID:
27189119
PMCID:
PMC5115998
DOI:
10.1038/ja.2016.44
[Indexed for MEDLINE]
Free PMC Article

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