1. BIOREpository

Biophysics and Bioinformatics of CRISPR/Cas and Toxin-Antitoxin Regulation

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Primary Data

Project title
Biophysics and Bioinformatics of CRISPR/Cas and Toxin-Antitoxin Regulation
Project Coordinator
Participant Organization(s)
 
Status
Completed
Start date
01-01-2022
Expected Completion
31-03-2025
 
Co-Investigator(s)

Description

Abstract
A major goal of the proposal is to understand how the spread of antibiotic resistance is affected by the dynamics and regulation of bacterial defense systems. Bacterial defense systems defend bacterial cells from acquired foreign DNA and include CRISPR/Cas, toxin-antitoxin, and restriction-modification systems (where the last two form a generalized ‘toxin-antitoxin’ group). As bacterial defense systems present a barrier to horizontal gene transfer, they have a major role in the spread of antibiotic resistance and virulence genes. The role of bacterial defense systems in the spread of antibiotic resistance is largely understudied and consequently not well understood. For example, CRISPR/Cas systems are often silent under standard conditions and it is unclear if they can be activated rapidly enough to protect the cell. Further, toxin-antitoxin systems may lead to persister formation by introducing bistability in bacterial cell growth. Such processes are highly non-linear and inherently quantitative. Moreover, different bacterial defense systems are often colocalized in bacterial defense islands, and evidence is emerging that they may act together in modulating the spread of antibiotic resistance. Consequently, to better understand some of the mechanisms for bacterial pathogenicity, a unified quantitative framework for dynamics and regulation of different bacterial defense systems is needed. We will here develop such a framework, by combining bioinformatics, biophysics (statistical thermodynamics), and non-linear dynamics (deterministic and stochastic) modeling to understand the underlying complex disease-related processes. The project will consequently generate a biophysical (quantitative) understanding of an important class of biological systems, necessary to guide future experiments and address a pressing global health problem.
 
Keyword(s)
bioinformatics; computational biology; bacterial defense systems; antibiotic resistance; CRISPR/Cas; restriction-modification systems; toxin-antitoxin systems; quantitative biology; theoretical biophysics; systems biology