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Optimization and mechanistic studies of halogenated phenazines and quinolines as anti-tuberculosis therapeutics

Award Number: R21AI159191
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/25/2021
PERIOD OF PERFORMANCE END DATE: 02/29/2024

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Optimization and mechanistic studies of halogenated phenazines and quinolines as anti-tuberculosis therapeutics - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = -$1 )
2024	2022	THE UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES	4000 CENTRAL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Allergy and Infectious Diseases Research	000	2	8/29/2024	NON-COMPETING CONTINUATION	-$1
														Subtotal = -$1

Issue Date FY: 2022 ( Subtotal = $190,125 )
2022	2022	UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES, THE	4000 CENTRAL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Allergy and Infectious Diseases Research	000	2	2/24/2022	NON-COMPETING CONTINUATION	$190,125
														Subtotal = $190,125

Issue Date FY: 2021 ( Subtotal = $241,150 )
2021	2021	UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES, THE	4000 CENTRAL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Allergy and Infectious Diseases Research	000	1	3/25/2021	NEW	$241,150
														Subtotal = $241,150

Grand Total All Awards = $431,274

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Optimization and mechanistic studies of halogenated phenazines and quinolines as anti-tuberculosis therapeutics

Award Number: R21AI159191

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/25/2021

PERIOD OF PERFORMANCE END DATE: 02/29/2024

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