PPE51 modulates membrane integrity in <i>Mycobacterium marinum</i>

The impermeable outer membrane of pathogenic mycobacteria presents a major obstacle to nutrient acquisition and antibiotic penetration. PPE51, a substrate of the ESX-5 secretion system, has previously been linked to glucose and glycerol uptake. Our study in <i>Mycobacterium marinum</i> reveals an unexpected additional role for PPE51 in maintaining membrane integrity. Loss of PPE51 not only impairs nutrient uptake but also causes increased membrane permeability, altered antibiotic susceptibility, and reduced virulence. These findings redefine PPE51 as more than a nutrient transporter, highlighting its broader role in cell envelope stability. This dual function has important implications for understanding how mycobacteria balance impermeability with metabolic needs and suggests new strategies to enhance antibiotic efficacy by targeting membrane-associated proteins like PPE51.