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Chalkophore mediated respiratory oxidase flexibility and M. tuberculosis virulence

Award Number: R01AI196228
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: 01/28/2026
PERIOD OF PERFORMANCE END DATE: 12/31/2029

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Chalkophore mediated respiratory oxidase flexibility and M. tuberculosis virulence - PROJECT SUMMARY Chalkophore mediated respiratory oxidase flexibility and M. tuberculosis virulence Diisonitrile lipopeptides are a novel class of copper-chelating natural products that are biosynthesized by non- ribosomal peptide synthetases found in a variety of Actinobacteria, including Mycobacterium tuberculosis, the bacteria that cause tuberculosis. In multiple studies, genetic disruption of the M. tuberculosis diisonitrile biosynthetic gene cluster attenuates bacterial virulence in mouse models of tuberculosis. This copper-binding activity identifies the diisonitriles as `chalkophores', which are structurally distinct from the well-known methanobactin chalkophores in methanotrophs. Further, we have shown that M. tuberculosis mutants in which chalkophore biosynthesis is disrupted are defective for growth in low-copper or copper-chelated media, and that this defect can be rescued by treatment with exogenous, synthetic diisonitriles, consistent with a role for diisonitriles in copper uptake. We have also shown that the diisonitrile chalkophore system is required to maintain the function of the copper-containing respiratory oxidase in low-copper culture and in mouse infection, establishing a specific physiologic target for diisonitrile chalkophore function and defining chalkophore mediated respiratory oxidase flexibility as an important virulence determine of M. tuberculosis. Further, the host immune pressure that targets M. tuberculosis respiration is independent of adaptive immunity. Building upon this work, in this proposal we will discover and characterize components of the chalkophore biosynthetic and handling systems using genetic, chemical biologic, and proteomic approaches. We will define the metal responsive transcriptional switch that controls respiratory oxidase flexibility and define the host pathways that target Mtb respiration during infection. This project will be carried out through a multidisciplinary collaboration led by Michael Glickman and Derek Tan comprising combined expertise in organic synthesis, organometallic chemistry, chemical biology, molecular biology, proteomics and microbial pathogenesis. Our long-term goals are to elucidate the roles of chalkophore mediated respiratory oxidase flexibility in M. tuberculosis pathogenesis and to understand the host factors that target the metal centers of the bacterial respiratory chain.


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: 2026 ( Subtotal = $3,178,476 )
2026	2026	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	1	1/28/2026	NEW	$3,178,476
														Subtotal = $3,178,476

Grand Total All Awards = $3,178,476

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Chalkophore mediated respiratory oxidase flexibility and M. tuberculosis virulence

Award Number: R01AI196228

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: 01/28/2026

PERIOD OF PERFORMANCE END DATE: 12/31/2029

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