Yukching Tse Dinh

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

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 compounds

Market 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)

Abstract

Prostate cancer is the second most frequently diagnosed cancer among men, being the leading cause of cancer mortality for elderly males. It can be effectively treated with a prostatectomy when detected early. However, when cancer metastasizes beyond the prostate it often treated with castration therapies. Although androgen deprivation therapy (ADT) through either chemical or surgical castration works initially to control metastatic prostate cancer, the cancer often progresses to treatment resistant prostate cancer, such as castration resistant prostate cancer (CRPC) or hormone refractory prostate cancer (HRPC). There is no efficient treatment for resistant prostate cancer, hence, 75% of patients die within the first five years of disease onset. Through research, it was identified that changes to the DNA damage and repair pathways are an essential part of prostate cancer progression to resistant prostate cancer. Moreover, the increased expression of DNA repair-associated genes and in particular base excision repair (BER)-associated genes is found to be a therapeutic target in most advanced prostate cancer. However, there have been no attempts to target core enzymes of BER in prostate cancer. FIU scientists have developed compositions and methods for treating prostate cancer by targeting DNA repair within cancer/tumor cells. The technology inhibits BER capacity in cancer cells without compromising normal cell growth, slowing down tumor growth and metastasis. Compared to currently available chemotherapy treatment options for castrate-resistant prostate cancer, these methods could provide an effective treatment with fewer side effects.

Benefit

Effective treatment for prostate cancer, including advanced prostate cancer using FDA approved drugsCan effectively block DNA repair in cancer cells without affecting normal cell growthReduce the recurrence of prostate cancerPrevent the progress and proliferation of prostate cancer cells

Market Application

Can be used for the prevention and treatment of prostate cancer, either early or advancedCould also be used in treating other cancers and relieving the symptoms of neurodegenerative disorders