title: β-Lactam antibiotics targeting PBP1 selectively enhance daptomycin activity against methicillin-resistant Staphylococcus aureus.
abstract: The activity of daptomycin (DAP) against methicillin-resistant Staphylococcus aureus (MRSA) is enhanced in the presence of subinhibitory concentrations of antistaphylococcal β-lactam antibiotics by an undefined mechanism. Given the variability in the penicillin-binding protein (PBP)-binding profiles of different β-lactam antibiotics, the purpose of this study was to examine the relative enhancement of DAP activity against MRSA by different β-lactam antibiotics to determine if a specific PBP-binding profile is associated with the ability to enhance the anti-MRSA activity of DAP. We determined that both broad- and narrow-spectrum β-lactam antibiotics known to exhibit PBP1 binding demonstrated potent enhancement of DAP anti-MRSA activity, whereas β-lactam antibiotics with minimal PBP1 binding (cefoxitin, ceftriaxone, cefaclor, and cefotaxime) were less effective. We suspect that PBP1 disruption by β-lactam antibiotics affects pathways of cell division in S. aureus that may be a compensatory response to DAP membrane insertion, resulting in DAP hypersusceptibility.
authors.affiliation: University of Wisconsin-Madison School of Pharmacy, Pharmacy Practice Division, Madison, Wisconsin, USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Berti
authors.forename: George
authors.initials: G
authors.lastname: Sakoulas
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
authors.forename: Ryan
authors.initials: R
authors.lastname: Tewhey
authors.forename: Warren E
authors.initials: WE
authors.lastname: Rose
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D017576:Daptomycin / Q000494:pharmacology*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D046915:Penicillin-Binding Proteins / Q000378:metabolism*; D011485:Protein Binding; D047090:beta-Lactams / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D046915:Penicillin-Binding Proteins; D047090:beta-Lactams; D017576:Daptomycin
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