Title : Development of formulations for novel chemotherapeutic agents for Tuberculosis and HIV coinfection
Background: Human immunodeficiency virus (HIV) has changed the global profile of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB). TB is the leading cause of death in AIDS patients worldwide. The apparent lethal synergy of TB with HIV has made the requirement for the development of new anti-TB and anti-HIV agents more imperative. Presently, the therapeutic management of HIV patients co-infected with Mtb poses great challenges because of drug-drug interactions and toxicity. Moreover, the emergence of multidrug resistant TB (MDR-TB) in HIV patients threatens to put an end to the efficacy of these drugs. Therapy for MDR-TB takes several years to complete, comprises of toxic second line drugs, and has high failure rates. Therefore, novel ways to treat HIV patients co-infected with TB are needed. Our research efforts have been focused on the development of formulations for new therapeutic agents for treatment of both TB and HIV infection. Our hypothesis is that therapeutically targeting TB and HIV with our novel inhibitors will treat and/or limit the progression and dissemination of these pathogens in co-infected patients.
Methods: While at the Johns Hopkins University School of Medicine, Dr. OmonikeOlaleye used a spectrophotometric assay to screen a library of 175,000 structurally diverse small molecules and identified novel potent inhibitors of M. tuberculosis. Following this analysis, we determined the potency of these inhibitors on HIV infectivity and developed a novel assay for the high-throughput screening (HTS) of inhibitors. Thereafter, we developed formulations for three new anti-TB-HIV chemotherapeutic agents.
Results: We characterized and developed formulations for potent novel compounds that have dual anti-TB and anti-HIV activity with safe pharmacologic profiles. The preliminary pharmacokinetic and cytotoxicity studies have shown promising results for the newly discovered compounds. Our results with the novel HTS assay has demonstrated the utility of this model to rapidly evaluate drug effectiveness relevant to cellular toxicity, HIV-1 replication, and intracellular mycobacterial growth.
Conclusion: The clinical significance of this study is that: The therapeutic targeting of TB-HIV activity in co-infected patients would accelerate the future development of new agents to treat drug-resistant TB and HIV infections in the clinic. Moreover, the development of a new formulation has great value in accelerating the discovery of new compounds for use in TB/HIV co-infected patients. Our results provide critical data with direct implications on efforts to control the global HIV and TB pandemics.
•The development of pre-formulations and formulations for these inhibitors against TB and HIV.
•The development of formulations for these inhibitors against TB and HIV.
•The development of a novel HTS assay for new small molecules targeting TB and HIV