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Target-based chemotherapeutics development against Mycobacterium tuberculosis

Award Number: R21AI142210
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: 07/01/2019
PERIOD OF PERFORMANCE END DATE: 06/30/2022

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Target-based chemotherapeutics development against Mycobacterium tuberculosis - Target-based chemotherapeutics development against Mycobacterium tuberculosis ABSTRACT Tuberculosis (TB) has been a global burden for thousands of years that is currently costing 1.6 million lives every year. The current therapies for TB are inadequate to control this epidemic and there is an urgent demand for the development of new effective anti-TB drugs, now more than ever, to overcome the problems of antimicrobial resistance. We have identified MraY as an attractive drug target, but one that is rather unexploited. MraY is essential for the biosynthesis of the peptidoglycan of bacterial cell walls. The limitations of current nucleoside MraY inhibitors are several: (i) poor in vivo efficacy; (ii) promiscuity (off-target activities); and (iii) accessibility only by semi-synthesis or total synthesis (>20 steps). We hypothesize that using structural insights on mechanism of MraY catalysis and inhibition, we could address those limitations and more importantly convert the existing broad-spectrum and promiscuous antibacterials to design new MraY inhibitors with narrow-spectrum activity against Mycobacterium tuberculosis (Mtb). The following aims will aid our discovery of new generations of anti-TB drugs that act through inhibition of MraY enzyme. Aim1. Develop MraY inhibitors as narrow-spectrum antibiotics against Mtb using structure-based design. We will utilize molecular modeling and docking studies on the recently published X-ray crystal structures of MraY from Aquifex aeolicus and Clostridium bolteae and design structurally simple analogues using a pharmacophore hybridization approach that will retain the key elements required for binding to the active site of MraY protein and critical for Mtb inhibitory activity. We will perform systematic structure-activity relationship studies to improve the inhibitory activity of the analogues against MraY and against replicating and multi-drug resistant Mtb strains. Aim 2. Identify new inhibitors of MraYMtb using protein-target-based virtual screening protocols. We will construct and validate homology models of MraYMtb using molecular dynamics simulations, which will be used to screen small molecule databases to identify and develop novel hits as MraY inhibitors. The outcome of these aims will establish a new strategy for TB therapy, where antibiotic resistance is impeding our ability to effectively control this epidemic. Notably, MraY is a validated target that is conserved in all bacteria and is not present in humans. Through this work, we will gain insight into how structure-based rational drug design strategies can be used effectively to convert broad-spectrum antibacterials to species-specific narrow-spectrum drug candidates and will provide a new therapeutic avenue for treatment of drug-sensitive and drug-resistant TB cases. This proposal will provide a critical step in treating other pathogenic and notoriously drug-resistant bacteria including methicillin-resistant Staphylococcus aureus, Vancomycon-resistant Enterococci, and Pseudomonas aeruginosa. The proposed research will advance the NIAID emphasis areas of basic and applied research to better understand, treat, and ultimately prevent infectious diseases.


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 = -$817 )
2024	2020	THE UNIVERSITY OF MISSISSIPPI	113 FALKNER	UNIVERSITY	MS	38677		USA	Allergy and Infectious Diseases Research	000	2	12/11/2023	NON-COMPETING CONTINUATION	-$817
														Subtotal = -$817

Issue Date FY: 2020 ( Subtotal = $218,138 )
2020	2020	UNIVERSITY OF MISSISSIPPI	113 FALKNER	UNIVERSITY	MS	38677		USA	Allergy and Infectious Diseases Research	000	2	6/25/2020	NON-COMPETING CONTINUATION	$218,138
														Subtotal = $218,138

Issue Date FY: 2019 ( Subtotal = $192,954 )
2019	2019	UNIVERSITY OF MISSISSIPPI	113 FALKNER	UNIVERSITY	MS	38677		USA	Allergy and Infectious Diseases Research	000	1	6/14/2019	NEW	$192,954
														Subtotal = $192,954

Grand Total All Awards = $410,275

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Target-based chemotherapeutics development against Mycobacterium tuberculosis

Award Number: R21AI142210

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: 07/01/2019

PERIOD OF PERFORMANCE END DATE: 06/30/2022

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