Mycobacteria are the causative agents of tuberculosis, leprosy, and NTM infections. They present a formidable therapeutic challenge because they possess a complex and largely impermeable cell envelope. This structure contains the essential mycolyl-arabinogalactan-peptidoglycan (mAGP) complex and is a primary determinant of intrinsic antibiotic resistance and pathogenesis.
Our laboratory investigates fundamental principles of mycobacterial physiology and host interaction. Focusing on the cell envelope, our research is organized around three aims.
First, we investigate how substrates are synthesized, transported, and incorporated to construct the cell envelope in mycobacteria. Complex lipid and glycan precursors are made within the cell but must traverse multiple layers of the envelope to reach their final sites of assembly. The lab studies the protein complexes involved in modifying and translocating these substrates.
Second, we investigate how the biogenesis of the mAGP complex is spatiotemporally orchestrated. This process must be tightly coordinated with cellular elongation and division. We study how the multi-protein assemblies—the elongasome and divisome—are recruited to sites of active growth, such as the cell poles and the division septum. We also aim to define the regulatory signals that govern these assemblies, ensuring the architectural integrity of the cell envelope throughout growth and division.
Third, we probe how the cell envelope functions as the primary host-pathogen interface. Mycobacteria use dedicated protein secretion systems to translocate proteins that interact with the host. The lab studies how these complex protein machines transport these effector proteins across the cell envelope and how these secreted effectors function in the host cell.
To address these questions, our lab combines bacterial genetics, biochemistry, and structural biology. Through this work, we aim to define the fundamental mechanisms of mycobacterial physiology. Our goal is to reveal new vulnerabilities for the development of novel treatments for this group of bacteria.