Absent new treatment options, bacteria evolve to develop resistance to existing drugs and spread rapidly across the globe. Thus, there is a strong need to identify drugs that: 1) act on bacterial pathogens via novel molecular targets, and 2) are chemically unrelated to clinically used antibiotics. Our innovative approach is designed to meet both of those criteria. Here we propose a novel, general platform to drug discovery that differs from both traditional phenotype- and target-based strategies, and requires a small fraction of the usual costs of drug discovery. Specifically, our proposed drug discovery platform leverages recent advances in bacterial systems biology and builds on large-scale analysis of the mechanisms of action of approved and experimental drugs developed for various indications. Three recent technological advances, coupled with the extensive relevant experience of the key personnel, underlie the proposal: (i) next-generation sequencing, transcriptomic, and metabolomic analyses support precise delineation of the mechanism of action for anti-bacterial drugs; (ii) recent commercial implementation of small molecule shape-comparison methods on GPUs dramatically increase the scale of problems amenable to accurate computational chemistry analysis; and (iii) careful curation of public resources and availability of proprietary databases of approved and experimental drugs enable analysis of large sets of clinical molecules with pre-defined properties. The innovative drug discovery platform proposed herein is designed to identify novel targets, and to discover and develop drugs to treat drug-resistant bacterial infections. In order to establish the feasibility of the approach, we propose to develop drugs working via novel mechanisms of action (MOA) against innately antibiotic-resistant Mycobacterium abscessus.

Public Health Relevance

Absent new treatment options, bacteria evolve to develop resistance to existing drugs and spread rapidly across the globe killing an estimated 700,000 people world-wide from drug- resistant infections in one year. Here we leverage recent advances in computational chemogenomics and bacterial systems biology to propose an innovative drug discovery platform designed to identify novel targets and to discover and develop drugs to treat drug-resistant bacterial infections. In order to establish the feasibility of the approach, we propose to develop drugs working via novel mechanisms of action against antibiotic-resistant Mycobacterium abscessus ? a major causative agent of difficult to treat pulmonary and surgical site infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI144386-02
Application #
10086955
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Boyce, Jim P
Project Start
2020-01-21
Project End
2021-12-31
Budget Start
2021-01-01
Budget End
2021-12-31
Support Year
2
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Trudeau Institute, Inc.
Department
Type
DUNS #
020658969
City
Saranac Lake
State
NY
Country
United States
Zip Code
12983