title: Efficacy of ampicillin against methicillin-resistant Staphylococcus aureus restored through synergy with branched poly(ethylenimine).
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.
authors.affiliation: Department of Chemistry and Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, Norman, OK, USA.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Foxley
authors.affiliation: Department of Chemistry and Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, Norman, OK, USA.
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Friedline
authors.affiliation: Department of Chemistry and Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, Norman, OK, USA.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Jensen
authors.affiliation: Department of Chemistry and Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, Norman, OK, USA.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Nimmo
authors.affiliation: Department of Chemistry and Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, Norman, OK, USA.
authors.forename: Erin M
authors.initials: EM
authors.lastname: Scull
authors.affiliation: Department of Chemistry and Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, Norman, OK, USA.
authors.forename: Jarrod B
authors.initials: JB
authors.lastname: King
authors.affiliation: Department of Chemistry and Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, Norman, OK, USA.
authors.forename: Stoffel
authors.initials: S
authors.lastname: Strange
authors.affiliation: Department of Chemistry and Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, Norman, OK, USA.
authors.forename: Min T
authors.initials: MT
authors.lastname: Xiao
authors.affiliation: Samuel Roberts Noble Microscopy Laboratory, University of Oklahoma, Norman, OK, USA.
authors.forename: Benjamin E
authors.initials: BE
authors.lastname: Smith
authors.affiliation: Department of Chemistry and Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, Norman, OK, USA.
authors.forename: Kieth J
authors.initials: KJ
authors.lastname: Thomas Iii
authors.affiliation: Department of Chemistry and Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, Norman, OK, USA.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Glatzhofer
authors.affiliation: Department of Chemistry and Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, Norman, OK, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Cichewicz
authors.affiliation: Department of Chemistry and Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, Norman, OK, USA.
authors.forename: Charles V
authors.initials: CV
authors.lastname: Rice
mesh_terms: D000667:Ampicillin / Q000737:chemistry / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D002473:Cell Wall / Q000187:drug effects / Q000378:metabolism; D004357:Drug Synergism; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D046915:Penicillin-Binding Proteins / Q000235:genetics / Q000378:metabolism; D011094:Polyethyleneimine / Q000737:chemistry / Q000494:pharmacology*; D013682:Teichoic Acids / Q000037:antagonists & inhibitors / Q000378:metabolism; D014640:Vancomycin / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D046915:Penicillin-Binding Proteins; D013682:Teichoic Acids; D014640:Vancomycin; D000667:Ampicillin; D011094:Polyethyleneimine