Grant: Project Grant - PA: Antimicrobial Resistance (Bridge Grant)

Mycobacteria, such as Mycobacterium tuberculosis (Mtb), are the deadliest bacterial pathogens, responsible for over 1.4 million deaths annually. One of the major reasons for the success of these pathogens is their unique and highly impermeable cell envelope, consisting of two membranes. While this envelope serves as a crucial barrier for survival during infection, conferring resistance to numerous antibiotics, it must simultaneously permit nutrient uptake and protein secretion for vital interactions with the host. To overcome these challenges, Mycobacteria have evolved a unique secretion system, the type VII secretion system (T7SS), as their main transport machinery that allows them to transport substrates, while maintaining the integrity of their cell envelope. Pathogenic mycobacteria, such as Mtb, have up to five subtypes of these secretion systems, named ESX-1 to ESX-5 and their substrates play distinct roles during infection, including preventing phagosome maturation, facilitating phagosome escape, inducing host cell death and manipulating the macrophage cytokine responses. While some substrates are important for virulence, others are essential for the uptake of specific metabolites that support mycobacterial growth. Therefore, the roles in virulence and viability make T7SS amongst the most versatile and important attributes of pathogenic mycobacteria. Elucidating the mechanism of T7S secretion and the role of individual effector proteins is therefore essential for understanding the success of pathogenic mycobacteria. Outcomes from this work could facilitate the identification of novel targets for drug and vaccine development.