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PPE51 modulates membrane integrity in Mycobacterium marinum
Vicky Charitou1, Beatriz Izquierdo Lafuente2, Eva Habjan1
1Department of Medical Microbiology and Infection Control, Amsterdam UMC, Location VU Medical Center, Amsterdam, the Netherlands.
Mbio
|September 22, 2025
Summary
PPE51 proteins are crucial for nutrient uptake and maintaining membrane integrity in mycobacteria. Loss of PPE51 function in Mycobacterium marinum impairs nutrient transport, increases permeability, and reduces virulence, highlighting its dual role.
Area of Science:
- Mycobacterial cell envelope biogenesis and function.
- Protein secretion systems in bacteria.
- Bacterial nutrient acquisition mechanisms.
Background:
- Mycobacteria possess a unique, impermeable outer membrane hindering nutrient uptake and antibiotic penetration.
- PPE proteins are mycobacteria-specific, secreted via type VII secretion systems.
- PPE51 was previously implicated in glucose and glycerol transport in Mycobacterium tuberculosis.
Purpose of the Study:
- To investigate the role of PPE51 proteins in nutrient uptake and membrane integrity in Mycobacterium marinum.
- To determine if PPE51's function in nutrient transport is conserved across mycobacterial species.
- To elucidate the broader function of PPE51 beyond nutrient transport.
Main Methods:
- Construction and analysis of single, double, and triple mutants of PPE51 paralogs in Mycobacterium marinum.
- Assessment of glucose and glycerol uptake in wild-type and mutant strains.
- Ethidium bromide influx assays to measure membrane permeability.
- Antibiotic susceptibility testing against high-molecular-weight antibiotics.
- Scanning electron microscopy for cell morphology analysis.
- Infection experiments using murine macrophages.
Main Results:
- The final PPE51 gene was essential for viability.
- PPE51's role in glucose and glycerol uptake was conserved in M. marinum.
- PPE51 proteins are substrates of the ESX-5 secretion system.
- Mutants lacking PPE51 exhibited increased membrane permeability and susceptibility to antibiotics like rifampicin and vancomycin.
- Triple mutants showed altered cell morphology and attenuated virulence in macrophages, linked to cell-wall integrity loss.
Conclusions:
- PPE51 plays a dual role in both nutrient uptake and maintaining mycobacterial membrane integrity.
- Loss of PPE51 function compromises cell envelope stability, leading to increased permeability and reduced virulence.
- These findings expand the known functions of PPE proteins and suggest PPE51 as a potential target for novel antimicrobial strategies.
