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Inhibition of methionine biosynthesis eliminates persistent M. tuberculosis.

Award Number: R21AI119573
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: 02/15/2016
PERIOD OF PERFORMANCE END DATE: 01/31/2019

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Inhibition of methionine biosynthesis eliminates persistent M. tuberculosis. - ¿ DESCRIPTION (provided by applicant): Mycobacterium tuberculosis is the most deadly bacterial pathogen in the world, killing 1.2 million people yearly and infecting over 8 million (WHO, 2013). Although chemotherapy against TB exists, a rapid global increase of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) cases makes new drugs with novel killing mechanisms an urgent need. A major drawback of current TB chemotherapy is its long duration, which increases the probability of relapse and the emergence of drug resistance. The underlying problem of this phenomenon is a population of non-replicating, drug-tolerant bacilli, the so-called persisters. However, current TB drugs are mainly effective against replicating and metabolically active bacteria. Preferably, new drugs kill fast (within weeks) and target actively growing as well as persister cells. Using a multidisciplinary approach, we have identified a novel drug target in methionine biosynthesis of M. tuberculosis. Our preliminary results are very promising, as they show rapid in vitro sterilization of a M. tuberculosis methionine auxotroph as well as complete lack of virulence in immunocompetent and immunocompromised mice. This is intriguing because most available TB antibiotics do not rapidly sterilize cultures. Metabolomics and transcriptomic analysis revealed a systemic metabolic shutdown by an unprecedented multi-target inhibition mechanism. The prospect of killing M. tuberculosis by causing rapid biosynthetic and metabolic seizure is very attractive for drug discovery. The goal of this proposal is to validate this drug target in vitro and in vivo and o develop a reporter strain for whole cell inhibitor screening. This will set the stage for a comprehensive high-throughput inhibitor screen against this target in the near future.


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: 2019 ( Subtotal = -$1,648 )
2019	2017	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	2	7/26/2019	NON-COMPETING CONTINUATION	-$1,648
														Subtotal = -$1,648

Issue Date FY: 2017 ( Subtotal = $208,750 )
2017	2017	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	2	1/6/2017	NON-COMPETING CONTINUATION	$208,750
														Subtotal = $208,750

Issue Date FY: 2016 ( Subtotal = $250,500 )
2016	2016	ALBERT EINSTEIN COLLEGE OF MEDICINE INC	111 E 210TH ST	BRONX	NY	10467	BRONX	USA	Allergy and Infectious Diseases Research	000	1	2/3/2016	NEW	$250,500
														Subtotal = $250,500

Grand Total All Awards = $457,602

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Inhibition of methionine biosynthesis eliminates persistent M. tuberculosis.

Award Number: R21AI119573

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: 02/15/2016

PERIOD OF PERFORMANCE END DATE: 01/31/2019

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