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 . There is an urgent need for potent drugs with novel modes of action able to kill
drug-resistant Mtb . 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.