Informing Drug Synergy: Investigating Mycobacterial Membrane Protein Structure and Function

The multi-layered cell envelope of Mycobacterium tuberculosis (Mtb) is a critical barrier to antibiotics and animportant target for drug development. Disrupting its assembly increases bacterial susceptibility to existingantibiotics creating opportunities for synergistic therapies. This proposal aims to elucidate the molecularmechanisms underlying envelope assembly focusing on key membrane proteins whose structures wehave determined. Aim 1 investigates the cytoplasmic synthesis and transport of mycolic acids essentialfatty acids in the mycomembrane by investigating the spatio-temporal localization of Pks13 and itsinteraction with fatty acid synthases. Aim 2 defines the physiological role of the essential efflux pump EfpAhypothesizing it functions as a lipid transporter and explores its inhibition as a therapeutic strategy. Aim 3characterizes proteins that coordinate mycomembrane biosynthesis particularly PgfA to understand howthis process is regulated for balanced cell growth. These studies will provide crucial insights into M.tuberculosis envelope construction paving the way for novel synergistic TB therapies that enhance theefficacy of existing treatments.