Research Project
7612508
DESCRIPTION (provided by applicant): In our previous work we identified a series of potent cell-wall inhibiting dipiperidines that are structurally unrelated to any existing antitubercular drugs. After extensive analysis of the lead molecules for anim- icrobial activity and drug properties compound SQ609 was selected as the most promising candidate: it has excellent in vivo activity, favorable pharmacological properties, and can be readily synthesized on a large scale. The overall aim of this SBIR Phase I application is to investigate potency, pharmacology, and potential toxicity of SQ609. Each of the proposed Specific Aims will provide decisive data to proceed with further development of SQ609 as an antitubercular. We will perform additional in vitro and in vivo microbiology studies to further characterize the potential of SQ609 as a new antitubercular drug. We will conduct in vivo efficacy studies in a mouse model of chronic TB infection to determine the most efficacious dose, evaluate the in vitro activity of SQ609 against drug-susceptible and drug-resistant clinical isolates of Mycobacterium tuberculosis (Mtb), determine the activity of SQ609 against non-replicating Mtb in vitro to assess the applicability of SQ609 in treating latent infection;evaluate the in vitro activity of SQ609 against Mtb in combination with the existing antitubercular drugs, as well as Sequella's TB drug candidate SQ109, in order to determine any synergistic, antagonistic, or additive effects. We will investigate the pharmacological properties of SQ609: stability evaluation in plasma and liver microsomes and plasma protein binding of SQ609;determination of pharmacokinetic parameters of SQ609 and bioavailability in mice following both IV and PO administration, and the tissue distribution profile of the drug in mice after single dosing. PUBLIC HEALTH RELEVANCE: Tuberculosis (TB) is the cause of the largest number of human deaths attributable to a single etiologic agent and the leading cause of death in those who are HIV-positive, accounting for 11% of the AIDS-related deaths worldwide. If one includes TB deaths in the HIV-co-infected population, nearly 3 million people die of TB each year. The current therapeutic regimen for TB recommended by the World Health Organization (WHO) requires the administration of four drugs for six months, which has a dismal compliance rate (30-60%) as a result of significant side effects and the inconvenience of daily therapy for such a long period of time. Decades of misuse of the existing antibiotics and poor compliance created an epidemic of drug resistance that now threatens TB control programs worldwide. In early 2006, clinicians began reporting the isolation of extensively drug resistant strains of TB (XDR-TB) that are resistant to the two most important front- line TB drugs, rifampicin and isoniazid, and also resistant to at least two classes of second-line drugs. New more potent drugs are desperately needed to shorten the regimen, treat drug-resistant infection, and to stem the rising tide of TB deaths. In our previous work we identified a series of potent cell-wall inhibiting dipiperidines that are structurally unrelated to any existing antitubercular drugs. After extensive analysis of the lead molecules for animicrobial activity and drug properties compound SQ609 was selected as the most promising candidate: it has excellent in vivo activity, favorable pharmacological properties, and can be readily synthesized on a large scale. The overall aim of this SBIR Phase I application is to investigate potency, pharmacology, and potential toxicity of SQ609. Each of the proposed Specific Aims will provide decisive data to proceed with further development of SQ609 as an antitubercular. The proposed studies are designed to address the criteria for a new TB therapeutic: 1) to provide a faster and more effective cure than the standard therapeutic regimen, 2) to improve the treatment of MDR- and XDR-TB;3) to develop treatments for latent infection. Under this SBIR Phase 1 funding we will perform additional in vitro and in vivo microbiology studies to further characterize the potential of SQ609 as a new antitubercular drug. We will investigate the pharmacological properties of SQ609 that will include stability evaluation in plasma and liver microsomes, plasma protein binding, as well as basic pharmacokinetic parameters, bioavailability, and the tissue distribution profile of SQ609 in mice following both IV and PO administration. Completion of these Specific Aims will provide vital data in support of development of SQ609 as an antitubercular and a firm rationale for determining whether or not to advance SQ609 into the extensive preclinical testing.
