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 antibioticsMarket Application
Optimization and development of new drugs against TB, non-tuberculosis mycobacteria (NTM) and other bacterial infections resistant to all current antibiotics
Abstract
Microbial pathogens are becoming increasingly resistant to
current antibiotics, limiting the availability of clinical treatment options
for bacterial infections. It is imperative to develop novel classes of
antibacterial compounds, preferably against a new target, to avoid
cross-resistance. Clinically, topoisomerase enzymes represent attractive and
successful targets for anticancer and antibacterial chemotherapy. Bacterial
topoisomerase I is a novel topoisomerase target that is essential for the
viability of pathogens including mycobacteria, Helicobacter pylori and
Pseudomonas aeruginosa.Researchers at FIU and the University of Hawai‘i have
synthesized fluoroquinophenoxazine analogs and demonstrated their activities as
topoisomerase I inhibitors and bactericidal antibacterial agents.Benefit
Offer a mechanism of action distinct from commercially available antibioticsProvide much needed treatment options for multi-drug resistant (MDR) bacterial pathogens that are resistant to currently available antibioticsCan be easily formulated into compositions together with pharmaceutically acceptable carriers for parenteral injection, solid or liquid form oral administration, and rectal administrationExhibit improved solubility characteristics as compared with prior quinolone-3-carboxylic acid compoundsMarket Application
Antibacterial drug development through in vitro cytotoxicity against mammalian cells and in vivo animal testingTreatment against bacterial pathogens, including both gram-positive and -negative bacteria such as coli, Staphylococcus aureus, Streptococcus pneumoniae, Helicobacter pylori, Mycobacterium bovis, Mycobacterium africanum, Mycobacterium microti, Mycobacterium canetti, Mycobacterium smegmatis, and Mycobacterium tuberculosisTreatment of infections in the form of biofilms formed by mycobacteria, including tuberculosis (Mtb) and nontuberculous mycobacteria (NTM)
