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

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.
AuthorsRichard 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, Jose A Ainsa, Helena I Boshoff, Mercedes Gonzalez-Juarrero, Bernd Meibohm, Erik C Böttger, Anne J Lenaerts
JournalNature medicine (Nat Med) Vol. 20 Issue 2 Pg. 152-158 (Feb 2014) ISSN: 1546-170X [Electronic] United States
PMID24464186 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • ATP-Binding Cassette Transporters
  • Amides
  • Antitubercular Agents
  • Bacterial Proteins
  • Rv1258c protein, Mycobacterium tuberculosis
  • Spectinomycin
Topics
  • ATP-Binding Cassette Transporters (metabolism)
  • Amides (chemical synthesis, chemistry, pharmacology)
  • Animals
  • Antitubercular Agents (chemical synthesis, chemistry, pharmacology)
  • Bacterial Proteins (metabolism)
  • Drug Design
  • Drug Resistance, Multiple, Bacterial (drug effects)
  • Mice
  • Models, Molecular
  • Mycobacterium tuberculosis (drug effects)
  • Ribosomes (drug effects)
  • Spectinomycin (chemistry, pharmacology)
  • Structure-Activity Relationship
  • Tuberculosis, Multidrug-Resistant (drug therapy)

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