Metabolic determinants of MTB virulence, vulnerability and variation

Ended Cooperative Agreement Awarded Last action

Award ID
U19AI162584
Recipient
Awarding agency
Obligated
$30,029,723

Award facts

Assistance listing
93.855 Allergy and Infectious Diseases Research
Completion date
Funding
  • $27,482,394.00 Federal
  • $2,547,329.00 Non-federal
Place of performance
Boston, MA 02115, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Metabolic determinants of MTB virulence, vulnerability and variation mycobacterium tuberculosis (MTB) has emerged as the world's most deadly pathogen based in large part on the highly unusual biological and chemical properties of its cell envelope. Comprised of a distinctive hydrophobic outer mycolate membrane, anchored to an underlying complex of polysaccharide and peptidoglycan polymers, the MTB envelope serves as both the primary interface with, and barrier to, the human host. In human tuberculosis (TB) disease the MTB envelope mediates a years-long standoff, and serves as the barrier to all anti-mycobacterial drugs. Yet, knowledge of its native composition, variation and regulation of drug entry remains fragmentary. This team of applicants has created new genetic and metabolomic tools to comprehensively dissect and analyze the metabolite and lipid components of the MTB envelope on an organism-wide basis across a large set of clinical isolates. Moreover, this tbru proposes to provide the first descriptions of cell envelope variation among isolates from human patients and identify key determinants of its virulence and barrier to drug action that could inform the development of better diagnostics and therapeutics. Structures of new molecules will first be determined using synthetic chemistry and mass spectrometry. The genes encoding these metabolites will then be identified and functionally validated using new genome-scale crispr interference technologies, assays for penetration into the cell envelope, and genetically defined mouse models of in vivo growth. Using mass spectrometry, we will solve the structures of up to 250 surface barrier lipids and more than 41 gene-lipid pairs that dominate in cell envelope variation among patients. Patient-derived MTB strains will be obtained from clinical samples collected at our field sites in masiphumelele, south africa, where we will implement clinically relevant technology for detection of live MTB in exhaled (non- coughed) human bioaerosols. Studies of barrier function place special emphasis on rifampicin as a model compound due to its clinical importance as a frontline drug and role as a defining element of drug resistant TB. The ability to analyze patient urine and serum has further resulted in the discovery of new biomarkers of disease activity and response to drug therapy, motivating linked translational efforts to advance the development of non-sputum based, real time point-of-care diagnostic tests. This highly interactive group of scientists thus seeks to provide better drugs and diagnostic tests, as well as a deep and durable scientific foundation for understanding of the MTB envelope, especially the particular genes and molecules that control active remodeling, drug action and human host response.

Transactions

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Amendment Metabolic adaptions of mycobacterium tuberculosis at diverse host-pathogen interfaces abstract defining the mechanisms through which mycobacterium… $543,819 $0
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Amendment Metabolic adaptions of mycobacterium tuberculosis at diverse host-pathogen interfaces abstract defining the mechanisms through which mycobacterium… $2,578,114 $0
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Original award $2,547,329 $2,547,329
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Subawards

Subrecipient Amount Awarded
Desmond Tutu Health Foundation Introduction and background. The Desmond Tutu Health Foundation (DTHF) operates an Aerobiology Research Center (ARC) in Masiphumele, Cape Town. The focus of the… $311,641
Duke University The proposed work will be done at Duke University, which is home to one of the national RBL facilities. As the PI of the project, Dr. Clare Smith is an… $524,069
Weill Medical College Of Cornell University We will characterize the impact of the frontline clinical drug rifampicin on the chemical structure and function of the cell wall of Mycobacterium tuberculosis.… $115,206
Rijksuniversiteit Groningen Introduction and background. To increase the rigor of analysis of bacterial compounds, Core C will provide existing synthetic compounds to benchmark metabolomic… $401,220
Weill Medical College Of Cornell University We will characterize the impact of the frontline clinical drug rifampicin on the chemical structure and function of the cell wall of Mycobacterium tuberculosis.… $193,854
Desmond Tutu Health Foundation Introduction and background. The Desmond Tutu Health Foundation (DTHF) operates an Aerobiology Research Center (ARC) in Masiphumele, Cape Town. The focus of the… $1,496,651
University Of Cape Town Introduction and background. The proposed TBRU project 2 is a collaborative project that will draw on the complementary skills of three research laboratories in… $653,975
Duke University Introduction and background. To functionally validate gene-metabolite pairs in vivo, Core E will conduct an array of M. tuberculosis aerosol infections in the… $1,053,340
The Rockefeller University The laboratory directed by Dr. Jeremy Rock will perform work described in the proposal entitled “Metabolic determinants of Mtb virulence, vulnerability… $2,263,686
Weill Medical College Of Cornell University We will characterize the impact of the frontline clinical drug rifampicin on the chemical structure and function of the cell wall of Mycobacterium tuberculosis.… $858,210
Weill Medical College Of Cornell University We will characterize the impact of the frontline clinical drug rifampicin on the chemical structure and function of the cell wall of Mycobacterium tuberculosis.… $1,578,674
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Quick answers

Who received award U19AI162584?

U19AI162584 was awarded to Brigham & Womens Hospital Inc. by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on July 1, 2021.

How much is award U19AI162584 worth?

$30,029,723 has been obligated on U19AI162584: $27,482,394 in federal funding and $2,547,329 in non-federal funding.

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