Antibacterial Compounds Targeting Bacterial Topoisomerase I – IP 1541

The topoisomerase I activity hasbeen shown to be essential for bacterial viability and infection in a murinemodel of tuberculosis. Tuberculosis (TB) infects 9.6 million people a year andcauses 1.5 million deaths each year. The problem presented by multi-drugresistance is illustrated by the 480,000 cases of multi-drug resistant TB(MDR-TB) that do not respond to first line treatment drugs, with around tenpercent of these cases being extensively-drug resistant tuberculosis (XDR-TB)that are resistant to even some of the second line drugs. Antibacterialcompounds targeting topoisomerase I as a novel target may be effective againstdrug resistant pathogens, including MDR-TB and XDR-TB that cannot be eliminatedby current antibiotics. Antibiotic resistance is also a major problem fortreating non-tuberculosis mycobacteria (NTM). However, many of the small molecules identified previously as bacterialtopoisomerase I inhibitors are DNA intercalators or minor groove binders, whichare not considered attractive candidates for antibiotics development. The inventors have developedcompounds of different molecular structures as inhibitors of mycobacteriatopoisomerase I activity and mycobacteria growth. Antibacterial assays demonstrated that thesecompounds are bactericidal against Mycobacterium smegmatis and Mycobacteriumtuberculosis. The minimal inhibitory concentrations for growth inhibition of M.smegmatis increased with overexpression of recombinant M. tuberculosistopoisomerase I, consistent with inhibition of intracellular topoisomerase Iactivity being involved in the antimycobacterial mode of action. Anne Laure Schmitt Olivier aschmitt@fiu.edu 305-348-5948