ArticleJournal of the American Chemical Society2015
The Tipper-Strominger Hypothesis and Triggering of Allostery in Penicillin-Binding Protein 2a of Methicillin-Resistant Staphylococcus aureus (MRSA).
Article in Journal of the American Chemical Society, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 35 citations in OpenAlex.
- Unraveling the mechanism of ceftaroline-induced allosteric regulation in penicillin-binding protein 2a: insights for novel antibiotic development against methicillin-resistantAntimicrobial agents and chemotherapy · 2023Article
- β-Lactams against the Fortress of the Gram-PositiveChemical reviews · 2021Review
- Unconventional Antibacterials and Adjuvants.Accounts of chemical research · 2021Article
- Fusidic acid resistance through changes in the dynamics of the drug target.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Exploration of the Structural Space in 4(3Journal of medicinal chemistry · 2020Article
- BPEI-Induced Delocalization of PBP4 Potentiates β-Lactams against MRSA.Biochemistry · 2019Article
- Thermosensitive PBP2a requires extracellular folding factors PrsA and HtrA1 forCommunications biology · 2019Article
- Peptidoglycan Cross-Linking Preferences of Staphylococcus aureus Penicillin-Binding Proteins Have Implications for Treating MRSA Infections.Journal of the American Chemical Society · 2017Article
- Conformational Dynamics in Penicillin-Binding Protein 2a of Methicillin-Resistant Staphylococcus aureus, Allosteric Communication Network and Enablement of Catalysis.Journal of the American Chemical Society · 2017Article
- Antimicrobial activity of ceftaroline against methicillin-resistant Staphylococcus aureus (MRSA) isolates collected in 2013-2014 at the Geneva University Hospitals.European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology · 2017Article
- β-Lactamases: A Focus on Current Challenges.Cold Spring Harbor perspectives in medicine · 2017Review
- β-Lactam Resistance Mechanisms: Gram-Positive Bacteria and Mycobacterium tuberculosis.Cold Spring Harbor perspectives in medicine · 2016Review
- Endless Resistance. Endless Antibiotics?MedChemComm · 2016Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
The transpeptidases involved in the synthesis of the bacterial cell wall (also known as penicillin-binding proteins, PBPs) have evolved to bind the acyl-D-Ala-D-Ala segment of the stem peptide of the nascent peptidoglycan for the physiologically important cross-linking of the cell wall. The Tipper-Strominger hypothesis stipulates that β-lactam antibiotics mimic the acyl-D-Ala-D-Ala moiety of the stem and, thus, are recognized by the PBPs with bactericidal consequences. We document that this mimicry exists also at the allosteric site of PBP2a of methicillin-resistant Staphylococcus aureus (MRSA). Interactions of different classes of β-lactam antibiotics, as mimics of the acyl-D-Ala-D-Ala moiety at the allosteric site, lead to a conformational change, across a distance of 60 Å to the active site. We directly visualize this change using an environmentally sensitive fluorescent probe affixed to the protein loops that frame the active site. This conformational mobility, documented in real time, allows antibiotic access to the active site of PBP2a. Furthermore, we document that this allosteric trigger enables synergy between two different β-lactam antibiotics, wherein occupancy at the allosteric site by one facilitates occupancy by a second at the transpeptidase catalytic site, thus lowering the minimal-inhibitory concentration. This synergy has important implications for the mitigation of facile emergence of resistance to these antibiotics by MRSA.
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