ArticleAntimicrobial agents and chemotherapy2012
Broadening the spectrum of β-lactam antibiotics through inhibition of signal peptidase type I.
Article in Antimicrobial agents and chemotherapy, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 77 citations in OpenAlex.
- Cyclization by Intramolecular Suzuki-Miyaura Cross-Coupling-A Review.Chemistry (Weinheim an der Bergstrasse, Germany) · 2025Review
- Unraveling the mechanism of small molecule induced activation of Staphylococcus aureus signal peptidase IB.Communications biology · 2024Article
- Unrealized targets in the discovery of antibiotics for Gram-negative bacterial infections.Nature reviews. Drug discovery · 2023Review
- Lipid Tales: Optimizing Arylomycin Membrane Anchors.ACS medicinal chemistry letters · 2023Article
- Novel antimicrobial strategies to treat multi-drug resistant Staphylococcus aureus infections.Microbial biotechnology · 2023Review
- Combining Signal Peptidase and Lipoprotein Processing Inhibitors Overcomes Ayr Resistance in Staphylococcus aureus.Antimicrobial agents and chemotherapy · 2023Article
- Naturally Occurring Organohalogen Compounds-A Comprehensive Review.Progress in the chemistry of organic natural products · 2023Review
- Antibacterial sensitizers from natural plants: A powerful weapon against methicillin-resistantFrontiers in pharmacology · 2023Review
- Reconstitution of theProceedings of the National Academy of Sciences of the United States of America · 2022Article
- Bacterial Signal Peptides- Navigating the Journey of Proteins.Frontiers in physiology · 2022Review
- Prospects for Antibacterial Discovery and Development.Journal of the American Chemical Society · 2021Article
- Amycolatomycins A and B, Cyclic Hexapeptides Isolated from anAntibiotics (Basel, Switzerland) · 2021Article
- Emerging peptide antibiotics with therapeutic potential.Medicine in drug discovery · 2021Review
- Tackling Antibiotic Resistance with Compounds of Natural Origin: A Comprehensive Review.Biomedicines · 2020Review
- Expanding the Spectrum of Antibiotics Capable of Killing Multidrug-Resistant Staphylococcus aureus and Pseudomonas aeruginosa.ChemMedChem · 2020Article
- Repurposing human kinase inhibitors to create an antibiotic active against drug-resistant Staphylococcus aureus, persisters and biofilms.Nature chemistry · 2020Article
- Article
- Scalable Access to Arylomycins via C-H Functionalization Logic.Journal of the American Chemical Society · 2018Article
- Tetracycline-Inactivating Enzymes.Frontiers in microbiology · 2018Review
- Article
Corrections and comments
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Authors and funding
33 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The resistance of methicillin-resistant Staphylococcus aureus (MRSA) to all β-lactam classes limits treatment options for serious infections involving this organism. Our goal is to discover new agents that restore the activity of β-lactams against MRSA, an approach that has led to the discovery of two classes of natural product antibiotics, a cyclic depsipeptide (krisynomycin) and a lipoglycopeptide (actinocarbasin), which potentiate the activity of imipenem against MRSA strain COL. We report here that these imipenem synergists are inhibitors of the bacterial type I signal peptidase SpsB, a serine protease that is required for the secretion of proteins that are exported through the Sec and Tat systems. A synthetic derivative of actinocarbasin, M131, synergized with imipenem both in vitro and in vivo with potent efficacy. The in vitro activity of M131 extends to clinical isolates of MRSA but not to a methicillin-sensitive strain. Synergy is restricted to β-lactam antibiotics and is not observed with other antibiotic classes. We propose that the SpsB inhibitors synergize with β-lactams by preventing the signal peptidase-mediated secretion of proteins required for β-lactam resistance. Combinations of SpsB inhibitors and β-lactams may expand the utility of these widely prescribed antibiotics to treat MRSA infections, analogous to β-lactamase inhibitors which restored the utility of this antibiotic class for the treatment of resistant Gram-negative infections.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.