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Spectinamides: a new class of semisynthetic antituberculosis agents that overcome native drug efflux

Nature Medicine volume 20, pages 152–158 (2014)Cite this article

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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.

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Figure 1: Spectinomycin and spectinamide ribosome binding.
Figure 2: In vivo efficacy trial data showing bacterial burden (log10 CFU) in the lungs of M. tuberculosis–infected mice. (a) Bacterial burden in the lungs of interferon-γ (IFN-γ) receptor knockout mice acutely infected with M. tuberculosis (n = 5) treated with lead spectinamides and comparator drugs all subcutaneously dosed at 200 mg per kg body weight twice daily (BID) for 9 d (mean ± s.

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Acknowledgements

This study was supported by US National Institutes of Health (NIH) grant AI090810 (R.E.L., E.C.B., A.J.L. and B.M.), the National Institute of Allergy and Infectious Diseases (NIAID) Indefinite Delivery Indefinite Quantity (IDIQ) (R.E.L. and M.G.) Contract Task Order HHSN272201000009I/01, the American Lebanese Syrian Associated Charities (ALSAC) and St. Jude Children's Research Hospital (SJCRH) (R.E.L.) and in part by the Intramural Research Program of the NIAID, NIH (H.I.B.) and the Spanish Government (grant BIO-2009-09405) (J.A.A.). We thank L. Yang and J. Scarborough from SJCRH for their help with analysis of the final compounds, M. Maddox from SJCRH for technical assistance in determining MIC values, J. Ryman from the University of Tennessee Health Science Center for technical assistance in the performance of pharmacokinetic studies in mice, M. Butler from Microbiotix for coordination of the MDR tuberculosis testing and E. Tuomanen from SJCRH for critical evaluation of this manuscript.

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Author notes

  1. Julian G Hurdle, Pavan K Vaddady & Cristina Villellas

    Present address: Present addresses: Department of Biology, University of Texas at Arlington, Arlington, Texas, USA (J.G.H.), Quantitative Pharmacology and Pharmacometrics, Merck Research Laboratories, Rahway, New Jersey, USA (P.K.V.) and Department of Antimicrobial Research, Janssen Infectious Diseases and Diagnostics BVBA, Johnson & Johnson, Turnhoutseweg, Beerse, Belgium (C.V.).,

  2. Julian G Hurdle, Jiuyu Liu, David F Bruhn, Tanja Matt and Michael S Scherman: These authors contributed equally to this work.

  3. Richard E Lee, Bernd Meibohm, Erik C Böttger and Anne J Lenaerts: These authors jointly directed this work.

Authors and Affiliations

  1. Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA

    Richard E Lee, Julian G Hurdle, Jiuyu Liu, David F Bruhn, Zhong Zheng, Jianjun Qi, Sourav Das, Robin B Lee,  Rakesh, Samanthi L Waidyarachchi & Dianqing Sun

  2. Institut für Medizinische Mikrobiologie, Nationales Zentrum für Mykobakterien, Universität Zürich, Zürich, Switzerland

    Tanja Matt, Rashid Akbergenov & Erik C Böttger

  3. Department of Microbiology, Mycobacterial Research Laboratories, Colorado State University, Fort Collins, Colorado, USA

    Michael S Scherman, Michael R McNeil, Mercedes Gonzalez-Juarrero & Anne J Lenaerts

  4. Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee, USA

    Pavan K Vaddady, Dora B Madhura, Chetan Rathi, Ashit Trivedi & Bernd Meibohm

  5. Departamento de Microbiología, Medicina Preventiva y Salud Pública, Universidad de Zaragoza, Zaragoza, Spain

    Cristina Villellas & Jose A Ainsa

  6. CIBER Enfermedades Respiratorias (CIBERES), Madrid, Spain

    Jose A Ainsa

  7. Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute for Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland, USA

    Helena I Boshoff

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  1. Richard E Lee
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Contributions

R.E.L. designed the compound series. J.G.H., D.F.B., R.B.L. and H.I.B. performed MIC testing and microbiology studies. J.L., J.Q., R., S.L.W. and D.S. performed the medicinal chemistry. T.M., R.A. and E.C.B. designed and performed MIC testing and ribosome inhibition studies. M.S.S., M.R.M., M.G.-J. and A.J.L. designed and performed the in vivo efficacy trials. P.K.V., C.R., D.B.M., A.T. and B.M. designed and performed the pharmacokinetic analysis. Z.Z. and S.D. performed the molecular modeling experiments. C.V., D.F.B. and J.A.A. designed and performed the efflux mutant testing. All authors discussed and analyzed the data. R.E.L., E.C.B., A.J.L., R.B.L., D.F.B., J.A.A. and B.M. wrote the manuscript.

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Correspondence to Richard E Lee.

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Competing interests

R.E.L., J.Q., J.G.H., B.M., P.K.V., R. and J.L. disclose intellectual property rights ownership associated with the spectinamide series.

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Supplementary Scheme 1, Supplementary Analytical Data, Supplementary Tables 1–12 and Supplementary Figures 1–3 (PDF 1822 kb)

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Lee, R., Hurdle, J., Liu, J. et al. Spectinamides: a new class of semisynthetic antituberculosis agents that overcome native drug efflux. Nat Med 20, 152–158 (2014). https://doi.org/10.1038/nm.3458

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