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Depleting Cationic Lipids Involved in Antimicrobial Resistance Drives Adaptive Lipid Remodeling in Enterococcus
Rafi Rashid1,2, Zeus Jaren Nair2,3,4, Dominic Ming Hao Chia2,4
1Integrative Sciences & Engineering Programme, National University of Singapore, Singapore.
Mbio
|January 11, 2023
Summary
The bacterial MprF enzyme modifies cell membranes to resist antimicrobial peptides. Its absence causes unexpected lipid changes, reduced membrane fluidity, and impaired protein secretion, highlighting MprF’s role in bacterial physiology.
Area of Science:
- Microbiology
- Biochemistry
- Cell Biology
Background:
- The bacterial cell membrane is crucial for various cellular processes and is a target for host defense mechanisms like cationic antimicrobial peptides (CAMPs).
- The multiple peptide resistance factor (MprF) enzyme confers resistance to CAMPs by modifying membrane phospholipids with cationic amino acids.
- In Enterococcus faecalis, MprF2 is the primary MprF paralog involved in resistance to human β-defensin 2 (hBD-2).
Purpose of the Study:
- To investigate the broader lipidomic and functional roles of MprF in Enterococcus faecalis.
- To understand the compensatory mechanisms within the bacterial lipidome in response to MprF activity or absence.
Main Methods:
- Comparative lipidomic analysis of wild-type and mprF mutant strains of E. faecalis.
- Assessment of bacterial growth in various media conditions, including fatty acid supplementation.
- Evaluation of membrane fluidity, protein secretion efficiency, and biofilm formation.
Main Results:
- MprF mutants, particularly the double mutant (ΔmprF1 ΔmprF2), showed a complete lack of cationic lysyl-phosphatidylglycerol (L-PG) and a reduction in phosphatidylglycerol (PG).
- Compensatory increases in glycerophospho-diglucosyl-diacylglycerol (GPDGDAG) and D-ala-GPDGDAG were observed in mprF mutants.
- Downregulation of fatty acid biosynthesis, accumulation of long-chain acyl-acyl carrier proteins (ACPs), decreased membrane fluidity, impaired protein secretion, and increased biofilm formation were associated with mprF mutations.
- Growth defects in the double mutant were partially rescued by exogenous fatty acids.
Conclusions:
- MprF plays a significant, previously unappreciated role in global lipid regulation and bacterial cellular physiology beyond CAMP resistance.
- Loss of L-PG triggers compensatory changes in the lipidome, affecting membrane properties and cellular functions.
- These adaptive mechanisms are critical for bacterial survival and must be considered when developing novel therapeutics targeting membrane lipids.
Keywords:
adaptive remodelingcationic antimicrobial peptides (CAMPs)lipid homeostasislipid metabolismlysyl-phosphatidylglycerol (L-PG)multiple peptide resistance factor (MprF)More Related Videos
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