期刊
NATURE MEDICINE
卷 20, 期 2, 页码 152-158出版社
NATURE PORTFOLIO
DOI: 10.1038/nm.3458
关键词
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资金
- US National Institutes of Health (NIH) [AI090810]
- National Institute of Allergy and Infectious Diseases (NIAID) Indefinite Delivery Indefinite Quantity (IDIQ)
- Contract Task Order [HHSN272201000009I/01]
- American Lebanese Syrian Associated Charities (ALSAC)
- St. Jude Children's Research Hospital (SJCRH)
- Intramural Research Program of the NIAID, NIH
- Spanish Government [BIO-2009-09405]
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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