Overview
We investigate infectious diseases caused by Mycobacterium species. These bacteria cause important diseases, including tuberculosis (TB) caused by Mycobacterium tuberculosis (Fig. 1), leprosy caused by Mycobacterium leprae, and non-tuberculous mycobacteria (NTM) diseases caused by related opportunistic pathogens such as Mycobacterium abscessus. Tackling infectious diseases like TB requires deep understanding of the pathogen’s biology, and our research is aimed at revealing the hidden strategies this pathogen uses to escape the body’s immune response and successfully propagate in humans.
Our research focuses on the surface coat of mycobacteria, which is composed of the plasma membrane (PM), peptidoglycan (PG) layer, arabinogalactan (AG) layer, outer membrane (OM), and extracellular capsule (Fig. 2). This multi-layered cell envelope is important to study because 1) it is a protective barrier against toxic molecules, such as antibiotics; 2) it consists of many molecules that may be recognized by host immune cells; and as a more fundamental cell biology question, 3) it maintains the rod shape of the cell.
Our research program pursues two major projects:
- Determine how mycobacteria maintain plasma membrane integrity and how we can explore plasma membrane as a drug target.
- Determine the physiological significance of lipoglycans in mycobacteria.
Recent accomplishments of our research program are summarized below:
1. Determine how mycobacteria maintain plasma membrane integrity and how we can explore plasma membrane as a drug target
- We revealed that the principles of plasma membrane organization are evolutionarily conserved in the TB pathogen (Puffal et al., 2022)
- We identified new proteins associated with a specific plasma membrane domain in Mycobacterium smegmatis, a model organism of mycobacteria research, using a novel imaging-based approach (Rokicki et al., 2021).
- We discovered that cell wall PG biosynthesis is driven by lateral membrane partitioning, which can be disrupted by perturbing cell wall integrity or plasma membrane fluidity (García-Heredia et al., 2021).
- We discovered that PonA2, a PG biosynthetic enzyme, facilitates the membrane compartmentalization in M. smegmatis (Kado et al., 2023).
- We discovered that Cfa, an enzyme involved in the biosynthesis of a mycobacteria-specific fatty acid known as tuberculostearic acid, is critical for maintaining membrane compartmentalization (Prithviraj et al., 2023).
- We discovered that mycobacteria respond to the membrane fluidizing stress by rapidly remodeling membrane glycolipids known as phosphatidylinositol mannosides (PIMs) (Nguyen et al., 2022).
2. Determine the physiological significance of lipoglycans in mycobacteria
- We discovered that lipomannan (LM) is maintained under stress conditions such as stationary growth phase or nutrient starvation while the levels of lipoarabinomannan (LAM) is decreased under these conditions (Rahlwes et al., 2020).
- We discovered that LAM plays a critical role in maintaining cell envelope integrity and regulate cell division and cell envelope elongation (Sparks et al., 2024).