Spectinomycin is a potent bacterial protein synthesis inhibitor yet has poor antimycobacterial activity. Spectinomycin was modified using structure based drug design to generate a novel series of 3'-substituted spectinamides. From the 140 spectinamides synthesized, a clear structure activity relationship has been established with respect to antitubercular activity and protein synthesis inhibition. Analogs with 2-heteroaryl acetic acid substitution displayed the best activities. From this panel, the most potent compounds showed M. tuberculosis MICs that are far superior to the MIC of Spectinomycin and comparable to Streptomycin. Lead spectinamides are not cross resistant to any current tuberculosis therapeutics. Key to their potent antitubercular properties was their structural modification to evade the Rv1258c efflux pump. In murine infection models, these spectinamides were well tolerated, significantly reduced lung tuberculosis burden alone and in combination with other agents.

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

247th National Meeting (2014)

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