Probing the structure-activity relationship of spectinomycin analogs in M. tuberculosis

Laura A. Wilt1, Jiuyu Liu1, Suresh Dharuman1, Chris Meyer1, Robin B. Lee1, Erick C. Böttger2, and Richard E. Lee1

1Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital
2Institut für Medizinische Mikrobiologie, Universität Zürich

Tuberculosis (TB) remains one of the top ten causes of death worldwide and remains a heavy burden in third world countries. Mechanisms of resistance exploited by the bacterium have led to the rise of multi-drug (MDR) and extensively-drug (XDR) TB worldwide. The aminocyclitol spectinomycin is a potent inhibitor of the bacterial protein synthesis but is subject to efflux by the MDR-transporter Rv1258c. To overcome efflux, the laboratory has developed semi-synthetic analogs of spectinomycin called spectinamides. These analogs show excellent narrow-spectrum anti-tubercular activity and successfully avoid Rv1258c-mediated transport; however, spectinamides are limited by their bioavailability. The spectinomycin binding site is highly coordinated by the hydrogen bonding network (Fig. 1) and remains a challenge for spectinamide optimization. Therefore, we probed the contribution of the synthesized 2- and 6-deoxy spectinomycin and spectinamide by molecular dynamic simulations followed by energy decomposition. The results from this study suggest that the 6-hydroxyl group is critical in antimicrobial activity in current analogs and the aryl side chains of spectinamides can rescue deoxy-analog activity.