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The role of Esx-3 in mediating drug resistance

Award Number: R01AI129360
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: 01/01/2020
PERIOD OF PERFORMANCE END DATE: 08/31/2024

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The role of Esx-3 in mediating drug resistance - Tuberculosis is a major cause of human suffering worldwide, with 1.8 million deaths and 10.4 million new cases in 2015. Although effective drug regimens for the treatment of TB exist, they are lengthy and involve multiple antibiotics to achieve sterilization and prevent relapse. The current treatment for TB is complex and lengthy requiring a minimum of six months with four drugs for the simplest of cases. It is not clear why drug therapy is so prolonged, although several theories relating to the physiological state of the bacteria have been proposed; these include the existence of drug-tolerant populations during infection, the presence of non-replicating (or slowly- replicating bacilli) and the lack of drug penetration to the sites of infection. Much recent effort has been expended in phenotypic screening to identify new molecular series for drug discovery and development; alongside which a chemical genomics approach has been taken to find novel drug targets using hit compounds identified in these screens. We are interested both in developing novel drugs and in understanding how such drugs work. We have identified a common mechanism of resistance to several, chemically-unrelated series in M. tuberculosis which involves mutation in a type VII secretion system (T7SS). We have identified compounds with interesting biological activities and which appear to work via similar mechanisms, or at least resistance is engendered by the same mechanism. Our proposal aims to determine the mode of action of these compounds. We propose that mode of action is via disruption of metal ion homeostasis with additional downstream effects, which would be a novel mechanism for future drug discovery efforts. We have identified mutations in several components of the Esx-3 T7SS (EccA3, EccB3, EccC3 and EccD3) which confer resistance to three compound series. It is unlikely that the Esx-3 system is the cellular target for these compounds, since mutations were found in four different genes, including one cytosolic protein that would not form part of the complex. Therefore it seems likely that resistance arises from a mechanism distinct from loss of compound-target binding. We propose to take a number of approaches combining microbiology, molecular biology and biochemistry to (i) determine the mode of action of compound series (ii) determine how the Esx- 3 T7SS can mediate compound resistance, and (iii) identify and characterize the targets of each series.


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: 2025 ( Subtotal = -$601 )
2025	2022	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	5	2/11/2025	NON-COMPETING CONTINUATION	-$601
														Subtotal = -$601

Issue Date FY: 2022 ( Subtotal = $464,998 )
2022	2022	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	5	8/18/2022	NON-COMPETING CONTINUATION	$464,998
														Subtotal = $464,998

Issue Date FY: 2021 ( Subtotal = $464,998 )
2021	2021	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	002	4	7/28/2021	NON-COMPETING CONTINUATION	$464,998
2021	2019	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	001	3	3/4/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$36,562
2021	2018	INFECTIOUS DISEASE RESEARCH INSTITUTE	1616 EASTLAKE AVE E STE 400	SEATTLE	WA	98102	KING	USA	Allergy and Infectious Diseases Research	000	1	3/4/2021	NEW	-$36,562
														Subtotal = $464,998

Issue Date FY: 2020 ( Subtotal = $29,748 )
2020	2019	SEATTLE CHILDREN'S HOSPITAL	4800 SAND PT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	001	3	5/25/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$464,998
2020	2019	INFECTIOUS DISEASE RESEARCH INSTITUTE	1616 EASTLAKE AVE E STE 400	SEATTLE	WA	98102	KING	USA	Allergy and Infectious Diseases Research	000	2	5/22/2020	NON-COMPETING CONTINUATION	-$435,250
														Subtotal = $29,748

Issue Date FY: 2019 ( Subtotal = $435,250 )
2019	2019	INFECTIOUS DISEASE RESEARCH INSTITUTE	1616 EASTLAKE AVE E STE 400	SEATTLE	WA	98102	KING	USA	Allergy and Infectious Diseases Research	000	2	7/29/2019	NON-COMPETING CONTINUATION	$435,250
														Subtotal = $435,250

Issue Date FY: 2018 ( Subtotal = $435,250 )
2018	2018	INFECTIOUS DISEASE RESEARCH INSTITUTE	1616 EASTLAKE AVE E STE 400	SEATTLE	WA	98102	KING	USA	Allergy and Infectious Diseases Research	000	1	8/27/2018	NEW	$435,250
														Subtotal = $435,250

Grand Total All Awards = $1,829,643

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The role of Esx-3 in mediating drug resistance

Award Number: R01AI129360

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: 01/01/2020

PERIOD OF PERFORMANCE END DATE: 08/31/2024

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