Chemical strategies to investigate mycomembrane remodeling and host interactions

The National Institute of Allergy and Infectious Diseases awarded the University of Massachusetts $797,682 on July 1, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to develop and apply chemical tools for investigating the structure and function of the mycobacterial outer membrane and its remodeling under stress and host interaction.

The award funds research to address knowledge gaps in mycobacterial membrane glycan and lipid biology, which have historically been difficult to study because these molecules are not genetically encoded and exhibit complex, heterogeneous structures. The investigators will develop clickable and fluorescence resonance energy transfer probes to elucidate mechanisms of stress-triggered membrane turnover and the interactions between membrane components and host cells. This work directly targets the mycobacterial outer membrane's role in Mycobacterium tuberculosis survival, virulence, and pathogenesis, with the goal of identifying therapeutic and preventive strategies against tuberculosis.

Performance occurs in Hadley, Massachusetts. The award runs from July 1, 2026, through June 30, 2031, as a Project Grant, a form of assistance funding supporting investigator-initiated research. The University of Massachusetts Office of Grant and Contract Administration is the administering entity.

Abstract

Mycobacterium tuberculosis, the causative agent of tuberculosis, remains the leading cause of death by a single infectious disease. The development of more effective therapeutic and prevention options for tuberculosis is an urgent priority. The outer mycomembrane that surrounds mycobacterial cells is a rich target because IT is essential for mycobacterial survival and virulence and is a significant permeability barrier. IT is also a "moving" target, in that the mycomembrane is remodeled upon host-mimicking stress and during infection. Understanding mycomembrane function is critical to realizing its therapeutic and preventative potential. However, key knowledge gaps persist regarding the molecular mechanisms by which mycomembrane components slow permeation and interact with the host, and how these properties change upon stress-triggered remodeling. A fundamental challenge to addressing these knowledge gaps has historically been the lack of suitable tools to study mycomembrane glycans and lipids, which are not directly genetically encoded. This problem is compounded by the complex, heterogeneous, and atypical structures of these macromolecules. To address these gaps, the investigators have developed chemical tools for labeling specific mycomembrane components with a variety of unnatural tags. Here, the investigators propose to apply these tools in new ways to understand mycomembrane chemistry and biology. In aim 1, they will make and use clickable and fret probes to determine mechanisms and vulnerabilities associated with stress-triggered mycomembrane turnover. In aim 2, they will make and use clickable, photocrosslinking probes to determine mechanisms by which mycomembrane components interact with and manipulate host cells. If successful, the proposed chemical strategies will enable the investigators-and the field as a whole-to pursue molecular- level, mechanistic understanding of mycomembrane remodeling, antibiotic permeability, and host interactions, in turn providing insights for urgently-needed therapeutic and preventative interventions.