Dynamics of the Acinetobacter baumannii inner membrane under exogenous polyunsaturated fatty acid stress
Hugo I MacDermott-Opeskin1, Alessandra Panizza1, Bart A Eijkelkamp2
1Research School of Chemistry, College of Science, Australian National University, Canberra, ACT, 2601, Australia.
Abstract:
Exogenous polyunsaturated fatty acids (PUFAs) are readily incorporated into the synthesis pathways of A. baumannii membrane phospholipids, where they contribute to reduced bacterial fitness and increased antimicrobial susceptibility. Here we examine the impact of PUFA membrane modification on membrane organisation and biophysical properties using coarse grained MARTINI simulations of chemically representative membrane models developed from mass-spectrometry datasets of an untreated, arachidonic acid (AA) treated and docosahexaenoic acid (DHA) treated A. baumannii membranes. Enzymatic integration of AA or DHA into phospholipids of the A. baumannii membrane resulted in modulation of membrane biophysical properties. Membrane thickness decreased slightly following PUFA treatment, concomitant with changes in the lateral area per lipid of each lipid headgroup class. PUFA treatment resulted in a decrease in membrane ordering and an increase in lipid lateral diffusion. Changes in lateral membrane organisation were observed in the PUFA treated membranes, with a concurrent increase in ordered cardiolipin domains and disordered PUFA-containing domains. Notably, separation between ordered and disordered domains was enhanced and was more pronounced for DHA relative to AA, providing a possible mechanism for greater antimicrobial action of DHA relative to AA observed experimentally. Furthermore, the membrane active antimicrobial, pentamidine, preferentially adsorbs to cardiolipin domains of the A. baumannii model membranes. This interaction, and membrane penetration of pentamidine, was enhanced following PUFA treatment. Cumulatively, this work explores the wide-ranging effects of PUFA incorporation on the A. baumannii membrane and provides a molecular basis for bacterial inner membrane disruption by PUFAs.
Insights
Polyunsaturated fatty acids (PUFAs) alter Acinetobacter baumannii membranes, decreasing thickness and increasing fluidity. This molecular change enhances antimicrobial drug effectiveness, offering new therapeutic strategies.
Area of Science:
- Microbiology
- Biophysics
- Computational Biology
Background:
- Acinetobacter baumannii is an opportunistic pathogen.
- Polyunsaturated fatty acids (PUFAs) incorporation into bacterial membranes affects bacterial fitness and antimicrobial susceptibility.
- Understanding PUFA effects on A. baumannii membranes is crucial for developing new treatments.
Purpose of the Study:
- To investigate the impact of polyunsaturated fatty acids (PUFAs) on the biophysical properties and organization of Acinetobacter baumannii membranes.
- To explore the molecular mechanisms underlying PUFA-mediated changes in membrane structure and function.
- To elucidate how PUFA modification influences the interaction of antimicrobials with the bacterial membrane.
Main Methods:
- Coarse-grained MARTINI simulations were employed to model A. baumannii membranes.
- Membrane models were developed from mass-spectrometry data of untreated, arachidonic acid (AA)-treated, and docosahexaenoic acid (DHA)-treated bacteria.
- Biophysical properties, membrane organization, and antimicrobial interactions were analyzed.
Main Results:
- PUFA incorporation (AA and DHA) modulated membrane biophysical properties, including decreased thickness and increased lipid lateral diffusion.
- Membrane ordering decreased, and lateral organization showed increased separation between ordered cardiolipin and disordered PUFA domains, more pronounced with DHA.
- The antimicrobial pentamidine showed enhanced adsorption to and penetration of PUFA-treated membranes, particularly interacting with cardiolipin domains.
Conclusions:
- PUFA modification significantly alters A. baumannii membrane organization and biophysical characteristics.
- These changes provide a molecular basis for enhanced antimicrobial susceptibility observed experimentally.
- The findings suggest a mechanism for increased antimicrobial action and potential therapeutic strategies targeting bacterial membranes.
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