U19AI162584

Metabolic Determinants of MTB Virulence, Vulnerability, and Variation - Abstract

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.

Brigham & Womens Hospital

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Boston, Massachusetts 021156110 United States

Single Zip Code

Tuberculosis Research Units (U19 Clinical Trial Optional) (RFA-AI-20-020)

Amendment Since initial award the total obligations have increased 429% from $2,547,329 to $13,485,680.