A5081326300- Tuberculosis Research and Epidemiology
- Mycobacterium research and diagnosis
- Computational Drug Discovery Methods
- CRISPR and Genetic Engineering
- Cancer therapeutics and mechanisms
- RNA and protein synthesis mechanisms
- Biochemical and Molecular Research
- Evolution and Genetic Dynamics
Cornell University
2017-2022
Weill Cornell Medicine
2021-2022
Antibacterial agents target the products of essential genes but rarely achieve complete inhibition. Thus, all-or-none definition essentiality afforded by traditional genetic approaches fails to discern most attractive bacterial targets: those whose incomplete inhibition results in major fitness costs. In contrast, gene "vulnerability" is a continuous, quantifiable trait that relates magnitude effect on fitness. We developed CRISPR interference-based functional genomics method systematically...
Mycobacterium tuberculosis (Mtb) infection is notoriously difficult to treat. Treatment efficacy limited by Mtb's intrinsic drug resistance, as well its ability evolve acquired resistance all antituberculars in clinical use. A deeper understanding of the bacterial pathways that influence could facilitate development more effective therapies, identify new mechanisms and reveal overlooked therapeutic opportunities. Here we developed a CRISPR interference chemical-genetics platform titrate...
Current chemotherapy against Mycobacterium tuberculosis (Mtb), an important human pathogen, requires a multidrug regimen lasting several months. While efforts have been made to optimize therapy by exploiting drug–drug synergies, testing new drug combinations in relevant host environments remains arduous. In particular, profoundly affect the bacterial metabolic state and efficacy, limiting accuracy of predictions based on vitro assays alone. this study, we utilized conditional Mtb knockdown...
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ABSTRACT Mycobacterium tuberculosis (Mtb) infection is notoriously difficult to treat. Treatment efficacy limited by Mtb’s intrinsic drug resistance, as well its ability evolve acquired resistance all antituberculars in clinical use. A deeper understanding of the bacterial pathways that govern could facilitate development more effective therapies overcome identify new mechanisms and reveal overlooked therapeutic opportunities. To define these pathways, we developed a CRISPR interference...
Chemical-genetics (C-G) experiments can be used to identify interactions between inhibitory compounds and bacterial genes, potentially revealing the targets of drugs, or other functionally interacting genes pathways. C-G involve constructing a library hypomorphic strains with essential that knocked-down, treating it an compound, using high-throughput sequencing quantify changes in relative abundance individual mutants. The hypothesis is that, if target drug same pathway are present library,...
Abstract Current chemotherapy against Mycobacterium tuberculosis ( Mtb ), an important human pathogen, requires a multidrug regimen lasting several months. While efforts have been made to optimize therapy by exploiting drug-drug synergies, testing new drug combinations in relevant host environments remains arduous. In particular, profoundly affect the bacterial metabolic state and efficacy, limiting accuracy of predictions based on vitro assays alone. this study, we utilize conditional...
New antibiotics are needed to combat rising resistance, with new Mycobacterium tuberculosis (Mtb) drugs of highest priority. Conventional whole-cell and biochemical antibiotic screens have failed. We developed a novel strategy termed PROSPECT (PRimary screening Of Strains Prioritize Expanded Chemistry Targets) in which we screen compounds against pools strains depleted for essential bacterial targets. engineered targeting 474 Mtb genes screened 100-150 activity-enriched unbiased libraries,...