Spectinamides: a new class of semisynthetic antituberculosis agents that overcome native drug efflux
| Autor: | Julian G. Hurdle, Rashid Akbergenov, Cristina Villellas, José A. Aínsa, Michael R. McNeil, Robin B. Lee, Jiuyu Liu, Dora B. Madhura, Erik C. Böttger, Rakesh, Zhong Zheng, Richard E. Lee, Bernd Meibohm, Pavan K. Vaddady, Jianjun Qi, Sourav Das, Samanthi L. Waidyarachchi, David F. Bruhn, Helena I. Boshoff, Michael S. Scherman, Dianqing Sun, Mercedes Gonzalez-Juarrero, Tanja Matt, Chetan Rathi, Anne J. Lenaerts, Ashit Trivedi |
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| Přispěvatelé: | University of Zurich, Lee, Richard E |
| Rok vydání: | 2014 |
| Předmět: |
Models
Molecular Spectinomycin Tuberculosis medicine.drug_class Antibiotics Antitubercular Agents 610 Medicine & health Drug resistance Biology Pharmacology Antimycobacterial Article General Biochemistry Genetics and Molecular Biology Microbiology Mice Structure-Activity Relationship 03 medical and health sciences Bacterial Proteins 1300 General Biochemistry Genetics and Molecular Biology Drug tolerance Drug Resistance Multiple Bacterial Tuberculosis Multidrug-Resistant medicine Animals 030304 developmental biology 0303 health sciences 10179 Institute of Medical Microbiology 030306 microbiology Drug discovery Mycobacterium tuberculosis General Medicine medicine.disease Amides 3. Good health Drug Design 570 Life sciences biology ATP-Binding Cassette Transporters Efflux Ribosomes medicine.drug |
| Zdroj: | Nature medicine |
| ISSN: | 1546-170X 1078-8956 |
| DOI: | 10.1038/nm.3458 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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