Research Project
10193679
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is responsible for staggering levels of global morbidity and mortality, with ~1.7 million deaths and ~10 million new cases each year. The shortcomings of currently available TB drugs hamper resolution of the ongoing TB crisis. The current ?short course? regimen involves a cocktail of four front-line drugs administered for 6-9 months. The emergence of drug-resistant Mtb strains has complicated the already difficult task of treating TB. Driven by patient noncompliance and poor drug efficacy, ~500,000 cases of Multidrug-Resistant TB (MDR-TB) occur each year that are resistant to the two first-line drugs rifampicin (RIF) and isoniazid (INH). There is also evidence of Extensively (XDR-TB) and Totally Drug Resistant Mtb (TDR-TB), which reduce the number of therapeutics to few and none, respectively [3]. There is an urgent need for potent drugs with novel modes of action able to kill drug-resistant Mtb [4]. The ability of Mtb to establish persistent, latent infections in which Mtb are sequestered within granulomas is a hallmark of TB disease. Recent studies suggest that conditions within this lesion (i.e., hypoxia, low pH) induce a dormant metabolic state that renders bacilli phenotypically drug tolerant. Very few compounds have been identified that are active against slow-growing, dormant ?persisters?. New drugs that will effectively eradicate such phenotypically resistant ?persisters? may be the key to shortening treatment regimens. Our discovery of novel natural-product inspired compounds known as halogenated phenazines (HPs) that exert potent, highly selective antimicrobial activity against Mycobacterium tuberculosis provides the premise for this project. In Aim 1, we will employ a pipeline of antimicrobial assays to evaluate a library of HP analogs as well as structurally related halogenated quinolines (HQs) to define structure-activity relationships and identify optimal lead compounds. We will also work to fully understand the unique mechanism of action of HPs and HQs which appear to kill bacteria by sequestration of cytoplasmic iron. In Aim 2, in vitro ADME and in vivo PK studies will inform medicinal chemistry optimization needs and progress top compounds towards in vivo efficacy studies. To achieve compounds with enhanced pharmacological properties and in vivo performance, we will also test prodrug analogs of the best lead compounds. Completion of the proposed specific aims will yield critical knowledge about the structure-activity relationships (SAR), ADME and PK properties and mechanism of action of the HP/HQ compounds that will serve as a foundation for future lead optimization and in vivo efficacy studies.
