ArticleACS infectious diseases2017
Structure-Activity Relationships of Spectinamide Antituberculosis Agents: A Dissection of Ribosomal Inhibition and Native Efflux Avoidance Contributions.
Article in ACS infectious diseases, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 57 citations in OpenAlex.
- Sterilizing activity of spectinamide MBX-4888A when replacing linezolid in the Nix-TB regimen in the relapsing BALB/c mouse model of tuberculosis.Antimicrobial agents and chemotherapy · 2025Article
- Revolutionizing tuberculosis treatment: Breakthroughs, challenges, and hope on the horizon.Acta pharmaceutica Sinica. B · 2025Review
- Development of tetracycline analogues with increased aqueous stability for the treatment of mycobacterial infections.Tuberculosis (Edinburgh, Scotland) · 2025Article
- Spectinamide MBX-4888A exhibits favorable lesion and tissue distribution and promotes treatment shortening in advanced murine models of tuberculosis.Antimicrobial agents and chemotherapy · 2024Article
- Enhancing the therapeutic window for Spectinamide anti-tuberculosis Agents: Synthesis, Evaluation, and activation of phosphate prodrug 3408.Bioorganic & medicinal chemistry letters · 2024Article
- A modified BPaL regimen for tuberculosis treatment replaces linezolid with inhaled spectinamides.eLife · 2024Article
- Synthesis and antibacterial action of 3',6'-disubstituted spectinomycins.The Journal of antibiotics · 2024Article
- Development of 2nd generation aminomethyl spectinomycins that overcome native efflux inProceedings of the National Academy of Sciences of the United States of America · 2024Article
- TargetingRSC medicinal chemistry · 2023Review
- Development of a Minimalistic Physiologically Based Pharmacokinetic (mPBPK) Model for the Preclinical Development of Spectinamide Antibiotics.Pharmaceutics · 2023Article
- Characterization of spectinamide 1599 efficacy against different mycobacterial phenotypes.Tuberculosis (Edinburgh, Scotland) · 2023Article
- Developing synergistic drug combinations to restore antibiotic sensitivity in drug-resistantAntimicrobial agents and chemotherapy · 2023Article
- Mab2780c, a TetV-like efflux pump, confers high-level spectinomycin resistance in mycobacterium abscessus.Tuberculosis (Edinburgh, Scotland) · 2023Article
- Biophysical analysis of the Mycobacteria tuberculosis peptide binding protein DppA reveals a stringent peptide binding pocket.Tuberculosis (Edinburgh, Scotland) · 2022Article
- Model-Based Exposure-Response Assessment for Spectinamide 1810 in a Mouse Model of Tuberculosis.Antimicrobial agents and chemotherapy · 2021Article
- Preclinical Evaluation of Inhalational Spectinamide-1599 Therapy against Tuberculosis.ACS infectious diseases · 2021Article
- Synthesis, antibacterial action, and ribosome inhibition of deoxyspectinomycins.The Journal of antibiotics · 2021Article
- Replacement of S14 Protein in Ribosomes of Zinc-Starved Mycobacteria Reduces Spectinamide Sensitivity.Antimicrobial agents and chemotherapy · 2021Article
- Antimycobacterial Activity, Synergism, and Mechanism of Action Evaluation of Novel Polycyclic Amines againstAdvances in pharmacological and pharmaceutical sciences · 2021Article
- Development of BODIPY FL Thalidomide As a High-Affinity Fluorescent Probe for Cereblon in a Time-Resolved Fluorescence Resonance Energy Transfer Assay.Bioconjugate chemistry · 2020Article
Corrections and comments
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Authors and funding
21 authors at 6 institutions in 3 countries.
Funding
Abstract
Spectinamides are a novel class of antitubercular agents with the potential to treat drug-resistant tuberculosis infections. Their antitubercular activity is derived from both ribosomal affinity and their ability to overcome intrinsic efflux mediated by the Mycobacterium tuberculosis Rv1258c efflux pump. This study explores the structure-activity relationships through analysis of 50 targeted spectinamides. Compounds are evaluated for ribosomal translational inhibition, MIC activity in Rv1258c efflux pump deficient and wild type tuberculosis strains, and efficacy in an acute model of tuberculosis infection. The results of this study show a narrow structure-activity relationship, consistent with a tight ribosome-binding pocket and strict structural requirements to overcome native efflux. Rationalization of ribosomal inhibition data using molecular dynamics simulations showed stable complex formation for halogenated spectinamides consistent with the long post antibiotic effects observed. The lead spectinamides identified in this study demonstrated potent MIC activity against MDR and XDR tuberculosis and had desirable antitubercular class specific features including low protein binding, low microsomal metabolism, no cytotoxicity, and significant reductions in bacterial burdens in the lungs of mice infected with M. tuberculosis. The structure-activity relationships detailed here emphasize the need to examine efflux-mediated resistance in the design of antituberculosis drugs and demonstrate that it is possible to overcome intrinsic efflux with synthetic modification. The ability to understand the structure requirements for this class has produced a variety of new substituted spectinamides, which may provide useful alternative candidates and promote the further development of this class.
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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.