Innovations in Genome Engineering

ORBITing into the Future​

TBSGC has achieved significant milestones in genome engineering such as the ORBIT method and optimization of recombineering techniques, enhancing core capabilities and enabling swift and selective genome modifications in Mtb, reflecting a commitment to advancing TB research and fostering transformative breakthroughs.

Our GOALS

Synergy-focused Research​

We aim to investigate fundamental biological mechanisms determining drug synergy in Mtb, define structural relationships between novel targets and chemical inhibitors for potential combination therapeutics, integrate drug interaction synergy into early drug discovery, determine structures of membrane proteins involved in drug mode of action, and discover early-stage chemical inhibitors synergistic with existing TB treatments and new therapeutics. Ultimately, the goal is to shift TB drug development towards targets and compounds likely to yield more effective combination regimens.

Our Projects

Each project is dedicated to exploring aspects of Mtb physiology characterized by established synergistic relationships.

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Exploiting synergistic vulnerabilities in the Mycobacterial cell envelope


- Identify, characterize, and optimize small molecules that inhibit prioritized cell wall synthetic targets.
- Investigate the mechanisms underlying synergy and test combinations in vivo.
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Structural and cellular studies on membrane proteins to inform drug synergy


- Structural and functional characterization of membrane proteins and complexes involved in envelope permeability and efflux
- Identify small molecule inhibitors of proteins involved in cell growth and division
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Targeting proteostasis for synergistic interactions


- Identify, characterize, and optimize small molecules that inhibit prioritized protein quality control targets.
- Develop a targeted protein degradation strategy using molecules that recruit to ClpX.

Our Cores

The Core research groups enhancing TBSGC with novel genetic, chemical, technical, and bioinformatic resources.

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Chemigenomics


- Mycobacterial genetics
- Target Identification
- Standardized bacterial and animal assays
- Quantitative cytology
- Bioinformatics
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Cryo-Electron Microscopy and Tomography


- Determine structures of large multicomponent complexes and membrane proteins of Mtb
-Solve Mtb macromolecular structures including large flexible multi-domain complexes and small proteins
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Chemical Biology


- Small molecule screens
- Hits assessment and early lead development
- DEL Screening and PROTAC molecules synthesis
- Virtual Screening
- Preliminary PK/PD Assessment
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Administrative


- Work with the PIs to manage, coordinate and supervise the projects and cores of the program
- Coordinate communications with NIAID and within the program
- Organize and coordinate steering committee meetings

Our Members

Sacchettini Lab

Texas A&M University

Rubin Lab

Harvard T.H Chan

Stroud Lab

UCSF Macromolecular Structure Group

Zhang Lab

Texas A&M University

Rego Lab

Yale School of Medicine

Ioerger Lab

Texas A&M University

Sassetti Lab

UMass Chan Medical School