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ACS Infect Dis. 2017 Jan 13;3(1):72-88. doi: 10.1021/acsinfecdis.6b00158. Epub 2016 Nov 11.

Structure-Activity Relationships of Spectinamide Antituberculosis Agents: A Dissection of Ribosomal Inhibition and Native Efflux Avoidance Contributions.

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Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital , 262 Danny Thomas Place, MS#1000, Memphis, Tennessee 38105, United States.
Institut für Medizinische Mikrobiologie, Nationales Zentrum für Mykobakterien, Universität Zürich , Rämistrasse 71, Gloriastrasse 30/32, CH-8006 Zürich, Switzerland.
Mycobacterial Research Laboratories, Department of Microbiology, Colorado State University , 1682 Campus Delivery, Fort Collins, Colorado 80523, United States.
Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute for Allergy and Infectious Disease, National Institutes of Health , 33 North Drive, Bethesda, Maryland 20814, United States.
Department of Pharmaceutical Sciences, University of Tennessee Health Science Center , 881 Madison Avenue, Memphis, Tennessee 38163, United States.
Departamento de Microbiologı́a, Medicina Preventiva y Salud Pública, and BIFI, Universidad de Zaragoza and CIBER Enfermedades Respiratorias (CIBERES) , 50009 Zaragoza, Spain.


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.


antituberculosis; efficacy; efflux pump; spectinamide; spectinomycin; structure−activity relationship

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