Abstract
The topoisomerase I activity has
been shown to be essential for bacterial viability and infection in a murine
model of tuberculosis. Tuberculosis (TB) infects 9.6 million people a year and
causes 1.5 million deaths each year. The problem presented by multi-drug
resistance 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 ten
percent of these cases being extensively-drug resistant tuberculosis (XDR-TB)
that are resistant to even some of the second line drugs. Antibacterial
compounds targeting topoisomerase I as a novel target may be effective against
drug resistant pathogens, including MDR-TB and XDR-TB that cannot be eliminated
by current antibiotics. Antibiotic resistance is also a major problem for
treating non-tuberculosis mycobacteria (NTM). However, many of the small molecules identified previously as bacterial
topoisomerase I inhibitors are DNA intercalators or minor groove binders, which
are not considered attractive candidates for antibiotics development.The inventors have developed
compounds of different molecular structures as inhibitors of mycobacteria
topoisomerase I activity and mycobacteria growth. Antibacterial assays demonstrated that these
compounds are bactericidal against Mycobacterium smegmatis and Mycobacterium
tuberculosis. The minimal inhibitory concentrations for growth inhibition of M.
smegmatis increased with overexpression of recombinant M. tuberculosis
topoisomerase I, consistent with inhibition of intracellular topoisomerase I
activity being involved in the antimycobacterial mode of action.
Benefit
Avoids drug resistance mechanisms of current antibiotics Can be used in combination with current antibiotics
Market Application
Optimization and development of new drugs against TB, non-tuberculosis mycobacteria (NTM) and other bacterial infections resistant to all current antibiotics
Brochure
