To make or take: bacterial lipid homeostasis during infection

Abstract

Bacterial fatty acids are critical components of the cellular membrane. A shift in environmental conditions or in the bacterium’s lifestyle may result in the requirement for a distinct pool of fatty acids with unique biophysical properties. This can be achieved by the modification of existing fatty acids or via de novo synthesis. Furthermore, bacteria have evolved efficient means to acquire these energy-rich molecules from their environment. However, the balance between de novo fatty acid synthesis and exogenous acquisition during pathogenesis is poorly understood. Here we studied the mouse fatty acid landscape prior and post infection with Acinetobacter baumannii, a Gram-negative, opportunistic human pathogen. The lipid fluxes observed following infection revealed fatty acid- and niche-specific changes. Lipidomic profiling of A. baumannii isolated from the pleural cavity of mice identified novel A. baumannii membrane phospholipid species and an overall increased abundance of unsaturated fatty acid species. Importantly, we found that A. baumannii relies largely upon fatty acid acquisition in all but one of the studied niches, the blood, where the pathogen biosynthesises its own fatty acids. This work is the first to reveal the significance of balancing the making and taking of fatty acids in a Gram-negative bacterium during infection, which provides new insights into the validity of targeting fatty acid synthesis as a treatment strategy.ImportanceAcinetobacter baumannii is one of the world’s most problematic superbugs, and is associated with significance morbidity and mortally in the hospital environment. The critical need for new antimicrobial strategies is recognised, but our understanding of its behaviour and adaptation to a changing environment during infection is limited. Here, we investigated the role of fatty acids at the host-pathogen interface using a mouse model of disease. We provide comprehensive insights into the bacterial membrane composition when they colonise the pleural cavity. Further, we show that A. baumannii heavily relies upon making its fatty acids when residing in the blood, whereas the bacterium favours fatty acid acquisition in most other host niches. Our new knowledge aids in understanding the importance of host fatty acids in infectious diseases. Further, fatty acid synthesis is an attractive target for the development of new antimicrobial strategies, but our work emphasizes the critical need to understand the microbial lipid homeostasis before this can be deemed suitable.

Structure and mechanism for streptococcal fatty acid kinase (Fak) system dedicated to host fatty acid scavenging

“…bacterial pathogen scavenges exogenous FAs for control of lipid homeostasis (20,25,26) or adaptation to host niches (27)(28)(29), is lacking.…”

Acinetobacter baumannii Fatty Acid Desaturases Facilitate Survival in Distinct Environments

“…Isolation of A. baumannii AB5075_UW from the BAL, PL or blood was performed as outlined previously . In brief, samples were diluted 10-fold into ice-cold PBS and centrifuged at 300 g for 10 min at 4 °C.…”

“…Isolation of A. baumannii AB5075_UW from the BAL, PL or blood was performed as outlined previously. 11 In brief, samples were diluted 10-fold into ice-cold PBS and centrifuged at 300g for 10 min at 4 °C. The bacterial cells in the supernatant were subsequently pelleted by centrifugation at 3000g for 15 min, washed in PBS, and transferred to QiaZol (Qiagen).…”

“…To ascertain if the regulome of DesT extends beyond that of desB ox B and hlyIII , a consensus motif was constructed, and additional putative binding sites across the A. baumannii AB5075_UW genome were determined (Table ). Sites included upstream of an operon which encodes a putative type I secretion system, comprised of a TolC family protein, HlyD family secretion protein, and two ABC transporter permeases (ABUW_0968–0965) and fadL (ABUW_0724), a recently characterized outer membrane protein required for acquisition of host-derived long chain fatty acids in A. baumannii . , Putative DesT binding sites located upstream of genes that were significantly differentially expressed in the desT ::T26 transcriptome were further examined by transcriptional profiling. Consistent with the transcriptomic data, desT inactivation resulted in derepression of desB ox B and hlyIII expression, and fadL downregulation (Figure C).…”

Loss of β-ketoacyl acyl carrier protein synthase III activity restores multidrug-resistantEscherichia colisensitivity to previously ineffective antibiotics

“…In bacteria, the essential acyl chains of PL and LPS are de novo synthesised by the highly conserved Type II Fatty Acid Synthesis pathway (FAS II) (11,12). The structural heterogeneity of acyl chains present in membrane lipids can determine how bacteria respond to challenging and fluctuating environments (13)(14)(15)(16)(17)(18)(19). As seen in other essential pathways, FAS II has evolved specialized components, which possess overlapping biochemical activities and complex redundancies.…”