P01AI181935

MICROBIOLOGY OF TREATMENT SHORTENING IN TUBERCULOSIS" - PROJECT SUMMARY/ABSTRACT - OVERALL EFFORTS TO ESTABLISH CONTROL OF THE TUBERCULOSIS (TB) PANDEMIC FACE HISTORICALLY UNPRECEDENTED CHALLENGES. IN THE WAKE OF COVID-19-INDUCED DISRUPTIONS IN TB HEALTHCARE-RELATED SERVICES, TB HAS RE-EMERGED AS THE LEADING CAUSE OF DEATHS DUE TO AN INFECTIOUS DISEASE WITH 2 CONSECUTIVE YEARS OF THE FIRST INCREASES IN TB MORTALITY SEEN IN OVER A DECADE. LACKING MORE EFFECTIVE AND SCALABLE TRANSMISSION BLOCKING INTERVENTIONS, CONTROL OF THE TB PANDEMIC WILL CONTINUE TO REST ON THE CLINICAL EFFICACY OF CHEMOTHERAPY. UNFORTUNATELY, WHILE STILL THERAPEUTICALLY EFFECTIVE AGAINST 95% OF NEWLY DIAGNOSED CASES, EXISTING CHEMOTHERAPIES HAVE PROVEN FUNCTIONALLY FAR LESS EFFECTIVE DUE TO THEIR TOXICITIES AND MONTHS-LONG DURATION. THIS PROGRAM PROJECT PROPOSES TO LAY A BASIC-SCIENCE FOUNDATION FOR DEVELOPING TREATMENT SHORTENING DRUGS AND REGIMENS. SUCH STUDIES ARE MOTIVATED BY THE EMPIRICAL DISCOVERY OF THE TREATMENT SHORTENING PROPERTIES OF RIFAMPIN AND PYRAZINAMIDE, TWO FRONTLINE AGENTS WHOSE ADDITION ENABLED A NEARLY 3-FOLD REDUCTION IN TREATMENT DURATION, AND MORE RECENT EVIDENCE IMPLICATING PHENOTYPICALLY DRUG-RESISTANT BACTERIAL SUBPOPULATIONS AS A BIOLOGICAL DETERMINANT OF TREATMENT DURATION. THIS APPLICATION BRINGS A SYNERGISTIC COMBINATION OF INVESTIGATORS AND DISCIPLINES TOGETHER FOR A COLLABORATIVE ATTACK THAT MOBILIZES NEW CONCEPTS, TECHNOLOGIES AND MODEL SYSTEMS TO DISCOVER AND TEST NEW TREATMENT SHORTENING TARGETS AND STRATEGIES. PROJECT 1 FOCUSES ON MECHANISMS THAT ALLOW THESE POPULATIONS TO PERSIST IN PATIENTS UNDERGOING CHEMOTHERAPY. PROJECT 2 FOCUSES ON REVERSE TRANSLATING THE TREATMENT SHORTENING ACTIVITIES OF RIFAMPIN AND PYRAZINAMIDE INTO IN VITRO BIOMARKERS, MECHANISMS AND TARGETS. PROJECT 3 WILL USE INNOVATIVE CRISPRI-BASED GENETIC-GENETIC INTERACTION MAPPING TO IDENTIFY HIGHLY EFFICACIOUS MTB DRUG-TARGET COMBINATIONS. PROJECT 4 EXPLOITS GENETIC APPROACHES TO DEFINE THE MTB GENE PRODUCTS WHOSE INACTIVATION HAS THE GREATEST POTENTIAL TO SHORTEN TB CHEMOTHERAPY. CORE A ENSURES THE EFFICIENT FLOW OF INFORMATION AND MATERIAL AMONG THESE PROJECTS. CORE B WILL COMBINE TECHNICAL ADVANCES IN SINGLE-CELL MEASUREMENT WITH DATA INTEGRATION APPROACHES TO ENABLE SINGLE CELL STUDIES OF HOW DIFFERENT SUBPOPULATIONS RESPOND TO TREATMENT AND/OR GENE INACTIVATION. CORE C WILL PROVIDE ACCESS TO A NOVEL PAUCIBACILLARY AND A DRUG TREATMENT MOUSE MODEL OF TB RELAPSE.

Weill Medical College Of Cornell University

NOT APPLICABLE

93.855 - Allergy and Infectious Diseases Research

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

New York, New York 100654805 United States

Single Zip Code

NIAID Investigator Initiated Program Project Applications (P01 Clinical Trial Not Allowed) (PAR-22-225)