Mycobacterial surface-mediated mechanical priming initiates spacious to compact phagosome switching for egress.

Mycobacterium tuberculosis (Mtb) establishes intracellular niches by remodeling host membranes into either spacious or compact phagosomes, yet how direct bacterial contact within these distinct compartments facilitates bacterial egress remains unknown. Using fixed cell imaging, reconstituted phagosome-like vesicles, and numerical simulations, we uncover that mycobacterial load-mediated contact determines phagosome fate by driving membrane-bending, lipid-wrapping, and phase-separation. Low-to-moderate bacterial loads promote membrane vesiculation and formation of compact phagosome-like structures, whereas high bacterial loads generate scaffold-like architectures that prime membranes for rupture by increasing deformability and inducing lipid demixing. Notably, direct bacterial contact further potentiates the membrane-disrupting activity of the virulence factor ESAT-6, synergistically compromising phagosomal integrity. We propose that mycobacteria actively control the dynamic balance between spacious and compact phagosomes by modulating host membrane mechanics through the membrane-to-contact area ratio and proximity to the lipid demixing threshold. Together, these findings identify a biophysical switch underlying pathogen-driven membrane remodeling and intracellular survival and escape.