ArticleProceedings of the National Academy of Sciences of the United States of America2015
Antiinfectives targeting enzymes and the proton motive force.
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 94 papers.
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Who cites it
94 citing papers in PubMed, 177 citations in OpenAlex.
- Proton Transfer Mechanisms in the MmpL3 Transporter ofACS bio & med chem Au · 2026Article
- Protective mechanism of action of the antifungal drug naftifine againstAntimicrobial agents and chemotherapy · 2026Article
- A two-step screen identifies a small molecule that disrupts membrane voltage and is effective against growing and persister gram-negative bacteria.Microbiology spectrum · 2026Article
- Inhibitors of NADH-O-methylquinone compound a class of antitubercular drugs.Molecular diversity · 2025Article
- Common Biological Properties ofACS infectious diseases · 2025Article
- A potent phenylalkylamine disrupts mycobacterial membrane bioenergetics and augments bactericidal activity of bedaquiline.iScience · 2025Article
- Broad-Spectrum Activity and Mechanisms of Action of SQ109 on a Variety of Fungi.ACS infectious diseases · 2025Article
- Efficacy of novel regimens targeting oxidative phosphorylation inAntimicrobial agents and chemotherapy · 2025Article
- Exploration of vanoxerine analogues as antibacterial agents.The Journal of antibiotics · 2025Article
- Sodium, Potassium-Adenosine Triphosphatase as a Potential Target of the Anti-Tuberculosis Agents, Clofazimine and Bedaquiline.International journal of molecular sciences · 2024Article
- Proton motive force and antibiotic tolerance in bacteria.Microbial biotechnology · 2024Review
- New functions of pirin proteins and a 2-ketoglutarate: Ferredoxin oxidoreductase ortholog in Bacteroides fragilis metabolism and their impact on antimicrobial susceptibility to metronidazole and amixicile.MicrobiologyOpen · 2024Article
- Discovery of new antimicrobial thiophene derivatives with activity against drug-resistant Gram negative-bacteria.Frontiers in pharmacology · 2024Article
- Mechanism of mycobacterial ATP synthase inhibition by squaramides and second generation diarylquinolines.The EMBO journal · 2023Article
- Investigation into the Mechanism of Action of the Tuberculosis Drug Candidate SQ109 and Its Metabolites and Analogues in Mycobacteria.Journal of medicinal chemistry · 2023Article
- Study of SQ109 analogs binding to mycobacterium MmpL3 transporter using MD simulations and alchemical relative binding free energy calculations.Journal of computer-aided molecular design · 2023Article
- Drug Repositioning as a Therapeutic Strategy againstInternational journal of molecular sciences · 2023Article
- Synthesis and Testing of Analogs of the Tuberculosis Drug Candidate SQ109 against Bacteria and Protozoa: Identification of Lead Compounds againstACS infectious diseases · 2023Article
- Vanoxerine kills mycobacteria through membrane depolarization and efflux inhibition.Frontiers in microbiology · 2023Article
- Making a chink in their armor: Current and next-generation antimicrobial strategies against the bacterial cell envelope.Advances in microbial physiology · 2023Article
34 more citing papers are in PubMed but not listed here.
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Authors and funding
16 authors at 5 institutions in 1 country.
Funding
Abstract
There is a growing need for new antibiotics. Compounds that target the proton motive force (PMF), uncouplers, represent one possible class of compounds that might be developed because they are already used to treat parasitic infections, and there is interest in their use for the treatment of other diseases, such as diabetes. Here, we tested a series of compounds, most with known antiinfective activity, for uncoupler activity. Many cationic amphiphiles tested positive, and some targeted isoprenoid biosynthesis or affected lipid bilayer structure. As an example, we found that clomiphene, a recently discovered undecaprenyl diphosphate synthase inhibitor active against Staphylococcus aureus, is an uncoupler. Using in silico screening, we then found that the anti-glioblastoma multiforme drug lead vacquinol is an inhibitor of Mycobacterium tuberculosis tuberculosinyl adenosine synthase, as well as being an uncoupler. Because vacquinol is also an inhibitor of M. tuberculosis cell growth, we used similarity searches based on the vacquinol structure, finding analogs with potent (∼0.5-2 μg/mL) activity against M. tuberculosis and S. aureus. Our results give a logical explanation of the observation that most new tuberculosis drug leads discovered by phenotypic screens and genome sequencing are highly lipophilic (logP ∼5.7) bases with membrane targets because such species are expected to partition into hydrophobic membranes, inhibiting membrane proteins, in addition to collapsing the PMF. This multiple targeting is expected to be of importance in overcoming the development of drug resistance because targeting membrane physical properties is expected to be less susceptible to the development of resistance.
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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.