Structure-activity relationships of spectinamide antituberculosis agents

A dissection of ribosomal inhibition and native efflux avoidance contributions

Jiuyu Liu, David F. Bruhn, Robin B. Lee, Zhong Zheng, Tanja Janusic, Dimitri Scherbakov, Michael S. Scherman, Helena I. Boshoff, Sourav Das, Rakesh, Samanthi L. Waidyarachchi, Tiffany A. Brewer, Begoña Gracia, Lei Yang, John Bollinger, Gregory T. Robertson, Bernd Meibohm, Anne J. Lenaerts, Jose Ainsa, Erik C. Böttger & 1 others Richard E. Lee

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)72-88
Number of pages17
JournalACS Infectious Diseases
Volume3
Issue number1
DOIs
StatePublished - Jan 1 2017

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Structure-Activity Relationship
Dissection
Multidrug-Resistant Tuberculosis
Mycobacterium tuberculosis
Tuberculosis
Antitubercular Agents
Drug Design
Molecular Dynamics Simulation
Infection
Ribosomes
Protein Binding
Anti-Bacterial Agents
Lung

All Science Journal Classification (ASJC) codes

  • Infectious Diseases

Cite this

Structure-activity relationships of spectinamide antituberculosis agents : A dissection of ribosomal inhibition and native efflux avoidance contributions. / Liu, Jiuyu; Bruhn, David F.; Lee, Robin B.; Zheng, Zhong; Janusic, Tanja; Scherbakov, Dimitri; Scherman, Michael S.; Boshoff, Helena I.; Das, Sourav; Rakesh; Waidyarachchi, Samanthi L.; Brewer, Tiffany A.; Gracia, Begoña; Yang, Lei; Bollinger, John; Robertson, Gregory T.; Meibohm, Bernd; Lenaerts, Anne J.; Ainsa, Jose; Böttger, Erik C.; Lee, Richard E.

In: ACS Infectious Diseases, Vol. 3, No. 1, 01.01.2017, p. 72-88.

Research output: Contribution to journalArticle

Liu, J, Bruhn, DF, Lee, RB, Zheng, Z, Janusic, T, Scherbakov, D, Scherman, MS, Boshoff, HI, Das, S, Rakesh, Waidyarachchi, SL, Brewer, TA, Gracia, B, Yang, L, Bollinger, J, Robertson, GT, Meibohm, B, Lenaerts, AJ, Ainsa, J, Böttger, EC & Lee, RE 2017, 'Structure-activity relationships of spectinamide antituberculosis agents: A dissection of ribosomal inhibition and native efflux avoidance contributions', ACS Infectious Diseases, vol. 3, no. 1, pp. 72-88. https://doi.org/10.1021/acsinfecdis.6b00158
Liu, Jiuyu ; Bruhn, David F. ; Lee, Robin B. ; Zheng, Zhong ; Janusic, Tanja ; Scherbakov, Dimitri ; Scherman, Michael S. ; Boshoff, Helena I. ; Das, Sourav ; Rakesh ; Waidyarachchi, Samanthi L. ; Brewer, Tiffany A. ; Gracia, Begoña ; Yang, Lei ; Bollinger, John ; Robertson, Gregory T. ; Meibohm, Bernd ; Lenaerts, Anne J. ; Ainsa, Jose ; Böttger, Erik C. ; Lee, Richard E. / Structure-activity relationships of spectinamide antituberculosis agents : A dissection of ribosomal inhibition and native efflux avoidance contributions. In: ACS Infectious Diseases. 2017 ; Vol. 3, No. 1. pp. 72-88.
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T2 - A dissection of ribosomal inhibition and native efflux avoidance contributions

AU - Liu, Jiuyu

AU - Bruhn, David F.

AU - Lee, Robin B.

AU - Zheng, Zhong

AU - Janusic, Tanja

AU - Scherbakov, Dimitri

AU - Scherman, Michael S.

AU - Boshoff, Helena I.

AU - Das, Sourav

AU - Rakesh,

AU - Waidyarachchi, Samanthi L.

AU - Brewer, Tiffany A.

AU - Gracia, Begoña

AU - Yang, Lei

AU - Bollinger, John

AU - Robertson, Gregory T.

AU - Meibohm, Bernd

AU - Lenaerts, Anne J.

AU - Ainsa, Jose

AU - Böttger, Erik C.

AU - Lee, Richard E.

PY - 2017/1/1

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AB - 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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