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A systems analysis of drug tolerance in Mycobacterium tuberculosis

Award Number: R01AI128215
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: 12/01/2016
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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A systems analysis of drug tolerance in Mycobacterium tuberculosis - PROPOSAL SUMMARY This project will address the critical need for accelerated development of multidrug regimen to achieve fast and complete clearance of Mycobacterium tuberculosis (Mtb), thereby lowering the likelihood for the emergence of antimicrobial resistance. Mtb dynamically adapts to extra- and intracellular host environments by adopting heterogeneous physiologic states, with varied susceptibility profiles to frontline antitubercular drugs. In the first four years of the R01, we have made progress towards dissecting this capability of Mtb by developing technologies to (i) uncover regulatory mechanisms that drive the pathogen into dormant states in host-simulated environments (controlled bioreactors) and directly within host cells (Path-seq), (ii) sort and characterize at single cell resolution translationally-dormant persister-like subpopulations within isogenic cultures (PerSort), (iii) uncover and characterize context-specific vulnerabilities within regulatory and metabolic networks (EGRIN2 and PRIME), and (iv) rationally formulate novel synergistic drug combinations (DRonA and MLSynergy). Using these capabilities and their applications reported across sixteen publications, we discovered that heterogeneous drug tolerant subpopulations co-exist within an isogenic culture of Mtb, even in the absence of drug treatment. Furthermore, we discovered that stressful environments and treatments activate additional drug tolerance networks, which may potentiate the emergence of resistance. Based on these findings, we hypothesize that we can achieve fast and complete clearance of Mtb infection with a combination of drugs that target vulnerabilities across heterogeneous drug tolerant subpopulations that co-exist in varied combinations and proportions depending on host- and treatment-contexts. To test this hypothesis, we will mechanistically characterize how the heterogeneous population structure of Mtb changes dynamically in response to host-relevant environmental cues and drug treatments. We will then uncover and characterize vulnerabilities within regulatory and metabolic networks that support and drive transitions to drug tolerant states. Using machine-learning techniques, we will predict and validate synergistic drug combinations targeting multiple vulnerabilities to cripple heterogeneous environment- and drug-induced states of Mtb. By performing time kill curves, we will investigate whether validated combinatorial interventions accomplish complete and faster clearance of heterogeneous Mtb subpopulations in diverse contexts. Altogether, the proposed activities will identify novel drug targets, and novel drug combinations for fast and complete clearance of a heterogeneous Mtb population. Given that phenotypic heterogeneity as a means for tolerating and resisting drugs is a universal phenomenon, the systems biology framework developed in this project will be generalizable to the discovery of effective multidrug regimen for diverse infectious diseases and even cancers.


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 = $841,703 )
2025	2025	INSTITUTE FOR SYSTEMS BIOLOGY	401 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	9	7/14/2025	NON-COMPETING CONTINUATION	$841,703
														Subtotal = $841,703

Issue Date FY: 2024 ( Subtotal = $868,716 )
2024	2024	INSTITUTE FOR SYSTEMS BIOLOGY	401 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	002	8	7/2/2024	NON-COMPETING CONTINUATION	$868,716
2024	2022	INSTITUTE FOR SYSTEMS BIOLOGY	401 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	001	6	2/7/2024	COMPETING CONTINUATION	$505,858
2024	2021	INSTITUTE FOR SYSTEMS BIOLOGY	401 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	5	2/7/2024	NON-COMPETING CONTINUATION	-$505,858
														Subtotal = $868,716

Issue Date FY: 2023 ( Subtotal = $886,311 )
2023	2023	INSTITUTE FOR SYSTEMS BIOLOGY	401 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	7	6/30/2023	NON-COMPETING CONTINUATION	$886,311
														Subtotal = $886,311

Issue Date FY: 2022 ( Subtotal = $904,421 )
2022	2022	INSTITUTE FOR SYSTEMS BIOLOGY	401 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	001	6	6/28/2022	COMPETING CONTINUATION	$904,421
2022	2021	INSTITUTE FOR SYSTEMS BIOLOGY	401 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	5	6/17/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $904,421

Issue Date FY: 2021 ( Subtotal = $913,527 )
2021	2021	INSTITUTE FOR SYSTEMS BIOLOGY	401 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	5	11/25/2020	NON-COMPETING CONTINUATION	$913,527
														Subtotal = $913,527

Issue Date FY: 2020 ( Subtotal = $848,588 )
2020	2020	INSTITUTE FOR SYSTEMS BIOLOGY	401 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	4	11/21/2019	NON-COMPETING CONTINUATION	$848,588
														Subtotal = $848,588

Issue Date FY: 2019 ( Subtotal = $902,060 )
2019	2019	INSTITUTE FOR SYSTEMS BIOLOGY	401 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	3	11/20/2018	NON-COMPETING CONTINUATION	$902,060
														Subtotal = $902,060

Issue Date FY: 2018 ( Subtotal = $912,707 )
2018	2018	INSTITUTE FOR SYSTEMS BIOLOGY	401 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	2	11/3/2017	NON-COMPETING CONTINUATION	$912,707
														Subtotal = $912,707

Issue Date FY: 2017 ( Subtotal = $871,572 )
2017	2017	INSTITUTE FOR SYSTEMS BIOLOGY	401 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	1	12/1/2016	NEW	$871,572
														Subtotal = $871,572

Grand Total All Awards = $7,949,605

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A systems analysis of drug tolerance in Mycobacterium tuberculosis

Award Number: R01AI128215

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: 12/01/2016

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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