NRSA for Isabel Sakarin: Rv3802c function in mycobacterial cell envelope remodeling, barrier properties, and antibiotic susceptibility

Project Summary/Abstract A quarter of the global population is infected with Mycobacterium tuberculosis, the causative agent of tuberculosis (TB). TB and other mycobacterial diseases are difficult to fight with immune responses or antibiotic therapy, largely due to the unique structure and composition of the mycobacterial cell envelope. The mycobacterial cell envelope contains more layers and more diverse lipids than other bacterial cell envelopes, which provides intrinsic resistance to common antibiotics that can treat other bacterial infections. To fight TB, we need therapeutic strategies that can overcome the unique barrier properties of the mycobacterial cell envelope. We therefore need to understand how to rationally disrupt that barrier. My project will address this need by using Rv3802c as an archetype to study the connection between biological function and the phenotypes of membrane properties and antibiotic susceptibility. Rv3802c is an essential protein with a putative role in cell envelope biosynthesis. I hypothesize that Rv3802c remodels the cell envelope to allow for the deposition of new cell envelope material, and that depletion of Rv3802c will decrease membrane fluidity and permeability to solutes and antibiotics. The goals of my project are to (1) characterize the biological function of Rv3802c and (2) determine Rv3820c’s role in regulating membrane barrier properties and antibiotic resistance. Connecting cell envelope biosynthesis to membrane barrier properties and antibiotic susceptibility will help fill in a vital gap in knowledge, ultimately paving the way for rational design of novel drugs and synergistic drug combinations.