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

Journal:
Nature medicine, Volume: 20, Issue: 2
Published:
February 26, 2014
PMID:
24464186
Authors:
Richard E Lee RE, Julian G Hurdle JG, Jiuyu Liu J, David F Bruhn DF, Tanja Matt T, Michael S Scherman MS, Pavan K Vaddady PK, Zhong Zheng Z, Jianjun Qi J, Rashid Akbergenov R, Sourav Das S, Dora B Madhura DB, Chetan Rathi C, Ashit Trivedi A, Cristina Villellas C, Robin B Lee RB, Rakesh , Samanthi L Waidyarachchi SL, Dianqing Sun D, Michael R McNeil MR, Jose A Ainsa JA, Helena I Boshoff HI, Mercedes Gonzalez-Juarrero M, Bernd Meibohm B, Erik C Böttger EC, Anne J Lenaerts AJ
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.