Description

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 resistance, 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. Spectinamides occupy the spectinomycin binding site at the interface of helix-34 of the bacterial 16S ribosomal RNA and the S5 protein loop. The aryl side chains on the analogs improve potency by increased protein-ligand and/or nucleotide-ligand interactions. Therefore, we hypothesize that adding polarity to the aryl chain on spectinamdies can increase favorable interactions with the S5 and S4 proteins to improve potency.