ArticleProceedings of the National Academy of Sciences of the United States of America2015
Antagonism screen for inhibitors of bacterial cell wall biogenesis uncovers an inhibitor of undecaprenyl diphosphate synthase.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 62 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
62 citing papers in PubMed, 104 citations in OpenAlex.
- Drug-microbiome-host interactions: antimicrobial effects of non-antibiotic compounds.Nature reviews. Gastroenterology & hepatology · 2026Review
- Host-Pathogen Dual Targeting With Repurposed Drugs Identifies a Synergistic Therapy for Intracellular Staphylococcus aureus.MicrobiologyOpen · 2026Article
- ThemBio · 2026Article
- Pardon the interruption: how Und-P sequestration has reshaped our understanding of the bacterial cell envelope.Journal of bacteriology · 2026Review
- Fighting the invader: strategies against intracellular bacteria.Frontiers in pharmacology · 2026Review
- Article
- Design, synthesis and optimization of TarO inhibitors as multifunctional antibiotics against Methicillin-resistant Staphylococcus aureus.npj antimicrobials and resistance · 2025Article
- Two codependent routes lead to high-level MRSA.Science (New York, N.Y.) · 2024Article
- Innovative Strategies in Drug Repurposing to Tackle Intracellular Bacterial Pathogens.Antibiotics (Basel, Switzerland) · 2024Review
- Bacillus subtilis uses the SigM signaling pathway to prioritize the use of its lipid carrier for cell wall synthesis.PLoS biology · 2024Article
- Lead generation of UPPS inhibitors targeting MRSA: Using 3D-QSAR pharmacophore modeling, virtual screening, molecular docking, and molecular dynamic simulations.BMC chemistry · 2024Article
- Chemical genetic approaches for the discovery of bacterial cell wall inhibitors.RSC medicinal chemistry · 2023Review
- Systematic analysis of drug combinations against Gram-positive bacteria.Nature microbiology · 2023Article
- Review
- Modulation of MRSA virulence gene expression by the wall teichoic acid enzyme TarO.Nature communications · 2023Article
- Synergistic Combinations of FDA-Approved Drugs with Ceftobiprole against Methicillin-Resistant Staphylococcus aureus.Microbiology spectrum · 2023Article
- Bacterial metabolism and susceptibility to cell wall-active antibiotics.Advances in microbial physiology · 2023Review
- Antibacterial sensitizers from natural plants: A powerful weapon against methicillin-resistantFrontiers in pharmacology · 2023Review
- Amoxicillin-resistanteLife · 2022Article
- Targeting the Holy Triangle of Quorum Sensing, Biofilm Formation, and Antibiotic Resistance in Pathogenic Bacteria.Microorganisms · 2022Review
2 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
Abstract
Drug combinations are valuable tools for studying biological systems. Although much attention has been given to synergistic interactions in revealing connections between cellular processes, antagonistic interactions can also have tremendous value in elucidating genetic networks and mechanisms of drug action. Here, we exploit the power of antagonism in a high-throughput screen for molecules that suppress the activity of targocil, an inhibitor of the wall teichoic acid (WTA) flippase in Staphylococcus aureus. Well-characterized antagonism within the WTA biosynthetic pathway indicated that early steps would be sensitive to this screen; however, broader interactions with cell wall biogenesis components suggested that it might capture additional targets. A chemical screening effort using this approach identified clomiphene, a widely used fertility drug, as one such compound. Mechanistic characterization revealed the target was the undecaprenyl diphosphate synthase, an enzyme that catalyzes the synthesis of a polyisoprenoid essential for both peptidoglycan and WTA synthesis. The work sheds light on mechanisms contributing to the observed suppressive interactions of clomiphene and in turn reveals aspects of the biology that underlie cell wall synthesis in S. aureus. Further, this effort highlights the utility of antagonistic interactions both in high-throughput screening and in compound mode of action studies. Importantly, clomiphene represents a lead for antibacterial drug discovery.
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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.