Modulation of Protein production and Degradation as an integrated approach to rapid sterilization of Drug sensitive and resistant Mtb.

Information

  • Research Project
  • 9674878
  • ApplicationId
    9674878
  • Core Project Number
    U19AI142735
  • Full Project Number
    1U19AI142735-01
  • Serial Number
    142735
  • FOA Number
    RFA-AI-17-042
  • Sub Project Id
  • Project Start Date
    4/1/2019 - 5 years ago
  • Project End Date
    3/31/2024 - 8 months ago
  • Program Officer Name
    PARKER, TINA M
  • Budget Start Date
    4/1/2019 - 5 years ago
  • Budget End Date
    3/31/2020 - 4 years ago
  • Fiscal Year
    2019
  • Support Year
    01
  • Suffix
  • Award Notice Date
    4/1/2019 - 5 years ago

Modulation of Protein production and Degradation as an integrated approach to rapid sterilization of Drug sensitive and resistant Mtb.

The main objective of the CETR is to modulate protein production and degradation as an integrated approach to rapid sterilization of drug sensitive (DS) and drug resistant tuberculosis (DR-TB) with the ultimate goal of delivering 2 investigational new drug (IND) applications and a regimen that will be effective against both DS and DR-TB and could result in relapse-free cures of TB-infected mice in 2 months or less, while also suppressing resistance development. Historically, TB treatment regimen development has been largely empiric. Our current treatment arises from serial clinical trials performed over the course of decades. Recently, we have accelerated this empiric process using a mouse model which, thus far, has excellent predictive power. However, any rationale for these regimens is ex post facto - we really do not understand why certain combinations are better than others. Here we will endeavor to devise a better regimen from first principles. We know that inhibition of RNA polymerase (RNAP) is clinically proven to shorten therapy dramatically and that rifampin synergizes with a variety of drugs. Using genetic studies, we have found that protein degradation is a particularly vulnerable process as even modest inhibition of Clp protease activity results in cell death. We reason that multiple insults in the ?proteostasis? pathway that leads from transcription through translation and protein turnover will likely result in more potent TB treatment regimens. Indeed, our preliminary in vivo data suggest this is true. This multidisciplinary CETR consortium will bring together key expertise on three major drug targets that constitute the complex and coordinated network of processes that maintain proteostasis in TB. Through this highly interconnected set of projects and cores we will be able to: Identify modulators of the Clp protease complex by discovering an orally active modulator of ClpC1, and a small molecule ClpP1P2 protease inhibitor (Project 1 and Project 2 and Cores A, B and C). Using structure guided drug discovery approaches and the latest formulation technologies these modulators will be optimized and advanced to preclinical candidate selection. We expect at least one preclinical candidate to emerge from these various approaches. Identify novel RNAP inhibitors that bind and inhibit the enzyme at a non-overlapping site than rifamycins that will therefore be effective against both drug-sensitive and DR-TB (Project 3 and Cores A, B, and C). Use of structural information and computational chemistry will guide our effort to preclinical candidate selection. Using an in vitro hollow fiber system and mouse Mtb-infection models, we will characterize the PK/PD relationships that govern the anti-TB activity and suppression of drug-resistant mutants for each drug candidate (ClpC1 modulators [Project 1], ClpP1P2 modulators [Project 2], RNAP inhibitors [Project 3] and a safer oxazolidinone already identified and currently in IND enabling studies, [Project 4]) and deliver the optimal universally active regimen.

IC Name
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
  • Activity
    U19
  • Administering IC
    AI
  • Application Type
    1
  • Direct Cost Amount
    5433792
  • Indirect Cost Amount
    51668
  • Total Cost
    5485460
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    855
  • Ed Inst. Type
  • Funding ICs
    NIAID:5485460\
  • Funding Mechanism
    Non-SBIR/STTR RPGs
  • Study Section
    ZAI1
  • Study Section Name
    Special Emphasis Panel
  • Organization Name
    GLOBAL ALLIANCE FOR TB DRUG DEVELOPMENT
  • Organization Department
  • Organization DUNS
    103139841
  • Organization City
    NEW YORK
  • Organization State
    NY
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    100051304
  • Organization District
    UNITED STATES