title: Molecular Bases Determining Daptomycin Resistance-Mediated Resensitization to β-Lactams (Seesaw Effect) in Methicillin-Resistant Staphylococcus aureus.
abstract: Antimicrobial resistance is recognized as one of the principal threats to public health worldwide, yet the problem is increasing. Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) strains are among the most difficult to treat in clinical settings due to the resistance of MRSA to nearly all available antibiotics. The cyclic anionic lipopeptide antibiotic daptomycin (DAP) is the clinical mainstay of anti-MRSA therapy. The decreased susceptibility to DAP (DAP resistance [DAPr]) reported in MRSA is frequently accompanied by a paradoxical decrease in β-lactam resistance, a process known as the "seesaw effect." Despite the observed discordance in resistance phenotypes, the combination of DAP and β-lactams has been proven to be clinically effective for the prevention and treatment of infections due to DAPrMRSA strains. However, the mechanisms underlying the interactions between DAP and β-lactams are largely unknown. In the study described here, we studied the role of mprF with DAP-induced mutations in β-lactam sensitization and its involvement in the effective killing by the DAP-oxacillin (OXA) combination. DAP-OXA-mediated effects resulted in cell wall perturbations, including changes in peptidoglycan insertion, penicillin-binding protein 2 (PBP 2) delocalization, and reduced membrane amounts of PBP 2a, despite the increased transcription of mecA through mec regulatory elements. We have found that the VraSR sensor-regulator is a key component of DAP resistance, triggering mutated mprF-mediated cell membrane (CM) modifications that result in impairment of PrsA location and chaperone functions, both of which are essential for PBP 2a maturation, the key determinant of β-lactam resistance. These observations provide for the first time evidence that synergistic effects between DAP and β-lactams involve PrsA posttranscriptional regulation of CM-associated PBP 2a.
authors: Hopitaux Universitaires de Genève, Service of Infectious Diseases, Geneva, Switzerland.
authors: Adriana
authors: A
authors: Renzoni
authors: University of Geneva Medical School, Department of Microbiology and Molecular Medicine, Geneva, Switzerland.
authors: William L
authors: WL
authors: Kelley
authors: Department of Pathology and Genomic Medicine, Center for Molecular and Translational Human Infectious Diseases Research, Houston Methodist Research Institute, Houston, Texas, USA.
authors: Roberto R
authors: RR
authors: Rosato
authors: Department of Pathology and Genomic Medicine, Center for Molecular and Translational Human Infectious Diseases Research, Houston Methodist Research Institute, Houston, Texas, USA.
authors: Maria P
authors: MP
authors: Martinez
authors: Department of Pathology and Genomic Medicine, Center for Molecular and Translational Human Infectious Diseases Research, Houston Methodist Research Institute, Houston, Texas, USA.
authors: Melanie
authors: M
authors: Roch
authors: Department of Pathology and Genomic Medicine, Center for Molecular and Translational Human Infectious Diseases Research, Houston Methodist Research Institute, Houston, Texas, USA.
authors: Maryam
authors: M
authors: Fatouraei
authors: Department of Microbiology and Molecular Genetics, McGovern Medical School, University of Texas, Houston, Texas, USA.
authors: Daniel P
authors: DP
authors: Haeusser
authors: Department of Microbiology and Molecular Genetics, McGovern Medical School, University of Texas, Houston, Texas, USA.
authors: William
authors: W
authors: Margolin
authors: Krebs Institute, University of Sheffield, Sheffield, United Kingdom.
authors: Samuel
authors: S
authors: Fenn
authors: Krebs Institute, University of Sheffield, Sheffield, United Kingdom.
authors: Robert D
authors: RD
authors: Turner
authors: Krebs Institute, University of Sheffield, Sheffield, United Kingdom.
authors: Simon J
authors: SJ
authors: Foster
authors: Department of Pathology and Genomic Medicine, Center for Molecular and Translational Human Infectious Diseases Research, Houston Methodist Research Institute, Houston, Texas, USA aerosato@HoustonMethodist.org.
authors: Adriana E
authors: AE
authors: Rosato
mesh_terms: D001426:Bacterial Proteins / Q000235:genetics; D017576:Daptomycin / Q000494:pharmacology*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000235:genetics; D008826:Microbial Sensitivity Tests; D009154:Mutation; D010068:Oxacillin / Q000494:pharmacology; D046915:Penicillin-Binding Proteins / Q000235:genetics; D047090:beta-Lactams / Q000494:pharmacology*
chemical_list: D001426:Bacterial Proteins; D046915:Penicillin-Binding Proteins; D047090:beta-Lactams; D017576:Daptomycin; D010068:Oxacillin
keywords: MRSA; PrsA; daptomycin; seesaw effect; β-lactams