Untangling the Inner Workings of the Mycobacterial Cell Envelope

Mycobacteria are the exception to many rules for bacteria. Their cellular structure and the way they grow defy common assumptions. Moreover, their exceptional cell biology is believed to underlie exceptional behaviors such as tolerance to drugs. Drug tolerance is general to mycobacteria, but is especially relevant to the eradication of pathogenic species such as non-tuberculous mycobacteria or NTM, which cause lung disease that is often refractory to current drugs. The unique characteristics of mycobacteria could offer attractive avenues for more effectively targeting them in infection. For example, their cell envelope is a multilayer cellular structure that is one of the most complex in the bacterial kingdom and contributes to the inherent resistance of mycobacteria to antibiotics. However, little is known about the properties of the cell envelope. In particular, little is known about adaptations of the outer membrane-like barrier known as the mycomembrane, which is a defining feature of mycobacteria due to its unusual composition and extreme hydrophobicity. The rationale of this proposal is that uncovering such fundamentals is essential to understanding mycobacterial adaptation and survival in the challenging environments that they encounter. The objective of this research program is to uncover how cell envelope organization responds to environmental factors. The proposal addresses three questions: Q1: How do mycobacteria adapt their surface proteins in response to environmental stress? Q2: How do mycobacteria transport lipoproteins to the cell surface and modulate lipoproteins in response to environmental stress? Q3: How do mycobacteria reorganize their membranes in response to environmental stress? The PI and team will address these questions through a combination of chemical biology, biophysics, and microbiology. A network of collaborations supports this program. The impact of this project is to provide (1) opportunities for the rational targeting of cell envelope biogenesis for anti-infective therapy and (2) much- needed tools to investigate mycobacterial membrane properties and cell envelope proteins. Project Number: 1R35GM164100-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Jessica Seeliger | Institution: STATE UNIVERSITY NEW YORK STONY BROOK, STONY BROOK, NY | Award Amount: $432,892 | Activity Code: R35 | Study Section: Special Emphasis Panel[ZRG1 MGG-D (55)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11331524