title: Penicillin Binding Protein 1 Is Important in the Compensatory Response of Staphylococcus aureus to Daptomycin-Induced Membrane Damage and Is a Potential Target for β-Lactam-Daptomycin Synergy.
abstract: The activity of daptomycin (DAP) against methicillin-resistant Staphylococcus aureus (MRSA) is enhanced in the presence of β-lactam antibiotics. This effect is more pronounced with β-lactam antibiotics that exhibit avid binding to penicillin binding protein 1 (PBP1). Here, we present evidence that PBP1 has a significant role in responding to DAP-induced stress on the cell. Expression of the pbpA transcript, encoding PBP1, was specifically induced by DAP exposure whereas expression of pbpB, pbpC, and pbpD, encoding PBP2, PBP3, and PBP4, respectively, remained unchanged. Using a MRSA COL strain with pbpA under an inducible promoter, increased pbpA transcription was accompanied by reduced susceptibility to, and killing by, DAP in vitro. Exposure to β-lactams that preferentially inactivate PBP1 was not associated with increased DAP binding, suggesting that synergy in the setting of anti-PBP1 pharmacotherapy results from increased DAP potency on a per-molecule basis. Combination exposure in an in vitro pharmacokinetic/pharmacodynamic model system with β-lactams that preferentially inactivate PBP1 (DAP-meropenem [MEM] or DAP-imipenem [IPM]) resulted in more-rapid killing than did combination exposure with DAP-nafcillin (NAF) (nonselective), DAP-ceftriaxone (CRO) or DAP-cefotaxime (CTX) (PBP2 selective), DAP-cefaclor (CEC) (PBP3 selective), or DAP-cefoxitin (FOX) (PBP4 selective). Compared to β-lactams with poor PBP1 binding specificity, exposure of S. aureus to DAP plus PBP1-selective β-lactams resulted in an increased frequency of septation and cell wall abnormalities. These data suggest that PBP1 activity may contribute to survival during DAP-induced metabolic stress. Therefore, targeted inactivation of PBP1 may enhance the antimicrobial efficiency of DAP, supporting the use of DAP-β-lactam combination therapy for serious MRSA infections, particularly when the β-lactam undermines the PBP1-mediated compensatory response.
authors.affiliation: Pharmacy Practice Division, University of Wisconsin-Madison School of Pharmacy, Madison, Wisconsin, USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Berti
authors.affiliation: Medical Scientist Training Program, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, USA Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: Theisen
authors.affiliation: Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: John-Demian
authors.initials: JD
authors.lastname: Sauer
authors.affiliation: Department of Biological Sciences, University of California San Diego, La Jolla, California, USA.
authors.forename: Poochit
authors.initials: P
authors.lastname: Nonejuie
authors.affiliation: Department of Biological Sciences, University of California San Diego, La Jolla, California, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Olson
authors.affiliation: Department of Biological Sciences, University of California San Diego, La Jolla, California, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Pogliano
authors.affiliation: Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, California, USA.
authors.forename: George
authors.initials: G
authors.lastname: Sakoulas
authors.affiliation: Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, California, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
authors.affiliation: Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, Wisconsin, USA Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Proctor
authors.affiliation: Pharmacy Practice Division, University of Wisconsin-Madison School of Pharmacy, Madison, Wisconsin, USA warren.rose@wisc.edu.
authors.forename: Warren E
authors.initials: WE
authors.lastname: Rose
mesh_terms: D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D002433:Cefaclor / Q000494:pharmacology; D002439:Cefotaxime / Q000494:pharmacology; D002440:Cefoxitin / Q000494:pharmacology; D002443:Ceftriaxone / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D017576:Daptomycin / Q000493:pharmacokinetics / Q000494:pharmacology*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D015964:Gene Expression Regulation, Bacterial; D015378:Imipenem / Q000493:pharmacokinetics / Q000494:pharmacology*; D000077731:Meropenem; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D015233:Models, Statistical; D009254:Nafcillin / Q000494:pharmacology; D046915:Penicillin-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D013845:Thienamycins / Q000493:pharmacokinetics / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D046915:Penicillin-Binding Proteins; D020033:Protein Isoforms; D013845:Thienamycins; D009254:Nafcillin; D002433:Cefaclor; D002440:Cefoxitin; D015378:Imipenem; D002443:Ceftriaxone; D000077731:Meropenem; D002439:Cefotaxime; D017576:Daptomycin