ArticlemBio2014
Novel determinants of antibiotic resistance: identification of mutated loci in highly methicillin-resistant subpopulations of methicillin-resistant Staphylococcus aureus.
Article in mBio, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 60 papers.
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Who cites it
60 citing papers in PubMed.
- An Achilles' heel for methicillin-resistantAntimicrobial agents and chemotherapy · 2026Review
- Mutation of lipoprotein processing pathway geneAntimicrobial agents and chemotherapy · 2026Article
- A Combined Aptamer Pulldown-DNAzyme Cleavage Assay for Intact Methicillin Resistant Staphylococcus aureus Cells.Angewandte Chemie (International ed. in English) · 2025Article
- The impact of bacterial purine metabolism on antibiotic efficacy.npj antimicrobials and resistance · 2025Review
- Resensitizing β-Lactams by Reprogramming Purine Metabolism in Small Colony Variant for Osteomyelitis Treatment.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Article
- Emergence of carbapenem resistance in persistent Shewanella algae bacteremia: the role of pdsS G547W mutation in adaptive subpopulation dynamics.Annals of clinical microbiology and antimicrobials · 2024Article
- Article
- The Spx stress regulator confers high-level β-lactam resistance and decreases susceptibility to last-line antibiotics in methicillin-resistantAntimicrobial agents and chemotherapy · 2024Article
- Methicillin-resistant Staphylococci in canine pyoderma in Thailand.Veterinary world · 2023Article
- Case Commentary: The hidden side of oxacillin resistance inAntimicrobial agents and chemotherapy · 2023Article
- Phenotypic and genomic characteristics of oxacillin-susceptible mecA-positive Staphylococcus aureus, rapid selection of high-level resistance to beta-lactams.European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology · 2023Article
- Molecular Determinants of β-Lactam Resistance in Methicillin-ResistantAntibiotics (Basel, Switzerland) · 2023Review
- Metabolic reprogramming and altered cell envelope characteristics in a pentose phosphate pathway mutant increases MRSA resistance to β-lactam antibiotics.PLoS pathogens · 2023Article
- Metabolic reprogramming and flux to cell envelope precursors in a pentose phosphate pathway mutant increases MRSA resistance to β-lactam antibiotics.bioRxiv : the preprint server for biology · 2023Article
- Article
- Molecular Characterization of Clinical Rel Mutations and Consequences for Resistance Expression and Fitness in Staphylococcus aureus.Antimicrobial agents and chemotherapy · 2022Article
- Molecular co-localization of multiple drugs in a nanoscopic delivery vehicle for potential synergistic remediation of multi-drug resistant bacteria.Scientific reports · 2022Article
- Genomic Basis of Occurrence of Cryptic Resistance among Oxacillin- and Cefoxitin-SusceptibleMicrobiology spectrum · 2022Article
- An Interplay of Multiple Positive and Negative Factors Governs Methicillin Resistance in Staphylococcus aureus.Microbiology and molecular biology reviews : MMBR · 2022Review
Corrections and comments
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Authors and funding
9 authors.
Funding
Abstract
We identified mutated genes in highly resistant subpopulations of methicillin-resistant Staphylococcus aureus (MRSA) that are most likely responsible for the historic failure of the β-lactam family of antibiotics as therapeutic agents against these important pathogens. Such subpopulations are produced during growth of most clinical MRSA strains, including the four historically early MRSA isolates studied here. Chromosomal DNA was prepared from the highly resistant cells along with DNA from the majority of cells (poorly resistant cells) followed by full genome sequencing. In the highly resistant cells, mutations were identified in 3 intergenic sequences and 27 genes representing a wide range of functional categories. A common feature of these mutations appears to be their capacity to induce high-level β-lactam resistance and increased amounts of the resistance protein PBP2A in the bacteria. The observations fit a recently described model in which the ultimate controlling factor of the phenotypic expression of β-lactam resistance in MRSA is a RelA-mediated stringent response. IMPORTANCE It has been well established that the level of antibiotic resistance (i.e., minimum concentration of a β-lactam antibiotic needed to inhibit growth) of a methicillin-resistant Staphylococcus aureus (MRSA) strain depends on the transcription and translation of the resistance protein PBP2A. Here we describe mutated loci in an additional novel set of genetic determinants that appear to be essential for the unusually high resistance levels typical of subpopulations of staphylococci that are produced with unique low frequency in most MRSA clinical isolates. We propose that mutations in these determinants can trigger induction of the stringent stress response which was recently shown to cause increased transcription/translation of the resistance protein PBP2A in parallel with the increased level of resistance.
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