Spectinamides

A new class of semisynthetic antituberculosis agents that overcome native drug efflux

Richard E. Lee, Julian G. Hurdle, Jiuyu Liu, David F. Bruhn, Tanja Matt, Michael S. Scherman, Pavan K. Vaddady, Zhong Zheng, Jianjun Qi, Rashid Akbergenov, Sourav Das, Dora B. Madhura, Chetan Rathi, Ashit Trivedi, Cristina Villellas, Robin B. Lee, Rakesh, Samanthi L. Waidyarachchi, Dianqing Sun, Michael R. McNeil & 6 others Jose A. Ainsa, Helena I. Boshoff, Mercedes Gonzalez-Juarrero, Bernd Meibohm, Erik C. Böttger, Anne J. Lenaerts

Research output: Contribution to journalArticle

81 Citations (Scopus)

Abstract

Although the classical antibiotic spectinomycin is a potent bacterial protein synthesis inhibitor, poor antimycobacterial activity limits its clinical application for treating tuberculosis. Using structure-based design, we generated a new semisynthetic series of spectinomycin analogs with selective ribosomal inhibition and excellent narrow-spectrum antitubercular activity. In multiple murine infection models, these spectinamides were well tolerated, significantly reduced lung mycobacterial burden and increased survival. In vitro studies demonstrated a lack of cross resistance with existing tuberculosis therapeutics, activity against multidrug-resistant (MDR) and extensively drug-resistant tuberculosis and an excellent pharmacological profile. Key to their potent antitubercular properties was their structural modification to evade the Rv1258c efflux pump, which is upregulated in MDR strains and is implicated in macrophage-induced drug tolerance. The antitubercular efficacy of spectinamides demonstrates that synthetic modifications to classical antibiotics can overcome the challenge of intrinsic efflux pump-mediated resistance and expands opportunities for target-based tuberculosis drug discovery.

Original languageEnglish (US)
Pages (from-to)152-158
Number of pages7
JournalNature Medicine
Volume20
Issue number2
DOIs
StatePublished - Feb 1 2014

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Spectinomycin
Tuberculosis
Pumps
Anti-Bacterial Agents
Protein Synthesis Inhibitors
Bacterial Proteins
Macrophages
Extensively Drug-Resistant Tuberculosis
Pharmaceutical Preparations
Drug Tolerance
Drug Discovery
Pharmacology
Lung
Infection
Therapeutics

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Lee, R. E., Hurdle, J. G., Liu, J., Bruhn, D. F., Matt, T., Scherman, M. S., ... Lenaerts, A. J. (2014). Spectinamides: A new class of semisynthetic antituberculosis agents that overcome native drug efflux. Nature Medicine, 20(2), 152-158. https://doi.org/10.1038/nm.3458

Spectinamides : A new class of semisynthetic antituberculosis agents that overcome native drug efflux. / Lee, Richard E.; Hurdle, Julian G.; Liu, Jiuyu; Bruhn, David F.; Matt, Tanja; Scherman, Michael S.; Vaddady, Pavan K.; Zheng, Zhong; Qi, Jianjun; Akbergenov, Rashid; Das, Sourav; Madhura, Dora B.; Rathi, Chetan; Trivedi, Ashit; Villellas, Cristina; Lee, Robin B.; Rakesh; Waidyarachchi, Samanthi L.; Sun, Dianqing; McNeil, Michael R.; Ainsa, Jose A.; Boshoff, Helena I.; Gonzalez-Juarrero, Mercedes; Meibohm, Bernd; Böttger, Erik C.; Lenaerts, Anne J.

In: Nature Medicine, Vol. 20, No. 2, 01.02.2014, p. 152-158.

Research output: Contribution to journalArticle

Lee, RE, Hurdle, JG, Liu, J, Bruhn, DF, Matt, T, Scherman, MS, Vaddady, PK, Zheng, Z, Qi, J, Akbergenov, R, Das, S, Madhura, DB, Rathi, C, Trivedi, A, Villellas, C, Lee, RB, Rakesh, Waidyarachchi, SL, Sun, D, McNeil, MR, Ainsa, JA, Boshoff, HI, Gonzalez-Juarrero, M, Meibohm, B, Böttger, EC & Lenaerts, AJ 2014, 'Spectinamides: A new class of semisynthetic antituberculosis agents that overcome native drug efflux', Nature Medicine, vol. 20, no. 2, pp. 152-158. https://doi.org/10.1038/nm.3458
Lee, Richard E. ; Hurdle, Julian G. ; Liu, Jiuyu ; Bruhn, David F. ; Matt, Tanja ; Scherman, Michael S. ; Vaddady, Pavan K. ; Zheng, Zhong ; Qi, Jianjun ; Akbergenov, Rashid ; Das, Sourav ; Madhura, Dora B. ; Rathi, Chetan ; Trivedi, Ashit ; Villellas, Cristina ; Lee, Robin B. ; Rakesh ; Waidyarachchi, Samanthi L. ; Sun, Dianqing ; McNeil, Michael R. ; Ainsa, Jose A. ; Boshoff, Helena I. ; Gonzalez-Juarrero, Mercedes ; Meibohm, Bernd ; Böttger, Erik C. ; Lenaerts, Anne J. / Spectinamides : A new class of semisynthetic antituberculosis agents that overcome native drug efflux. In: Nature Medicine. 2014 ; Vol. 20, No. 2. pp. 152-158.
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