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Bacterial lipocalins: Novel role in bacterial protection against antibiotic-induced membrane lipid peroxidation

   School of Medicine, Dentistry & Biomedical Sciences

  Prof M Valvano  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

We recently discovered that bacteria can resist antibiotics by mechanisms operating extracellularly in response to near-lethal antibiotic concentrations. This means microbes fight antibiotics even before they reach bacterial cells. Key molecules involved in this mechanism are the polyamine putrescine and lipocalins (LP), a highly conserved group of barrel-shaped proteins of unknown function produced by >6,500 bacterial species. We demonstrated LPs scavenge different classes of antibiotics from the extracellular milieu. Also, LPs bind isoprenoids (e.g. octaprenyl-phosphate) into the interior of the barrel, while low-affinity antibiotic binding occurs at the rim of the molecule. The physiological role of LPs remains unknown. Bacteria exposed to near-lethal antibiotic concentrations (e.g. during treatment of chronic and biofilm infections), also mount an oxidative response, which in turn stimulates transcription of LP encoding genes. We have now discovered that bacterial mutants defective in LP production display enhanced membrane lipid peroxidation and fail to survive under conditions that stimulate peroxidative stress. This means that LPs may have a novel role in protecting bacteria against toxic byproducts of lipid peroxidation. How bacterial cells overcome lipid peroxidation, especially the double membraned Gram-negatives, is virtually unknown. Our experimental results bridge this knowledge gap and uncover LPs as components of a novel mechanism to protect bacterial cell membranes from lipid peroxidative damage. This programme will address two questions: (i) What are the structure-function properties of diverse LPs involved in antibiotic binding and protection against lipid peroxidation? and (ii) What other bacterial components are needed for protection against lipid peroxidation? The model bacteria employed are the Gram-negative members of the ESKAPE group, namely Klebsiella, Acinetobacter, Pseudomonas and Enterobacter species. This research project combines molecular microbiology, biochemistry, metabolomics, bioinformatics, and infection models to elucidate the role of LPs in antibiotic binding and in maintaining the homeostasis of the bacterial membranes under oxidative stress, commonly found upon exposure to near-lethal doses of antibiotics.

The PhD student will investigate the function of LPs in the bacterial defences against lipid peroxidation by tackling 3 aims:

1. To determine the structure-function of LP and its secretion state in protection against lipid peroxidation

2. To identify and characterise additional components to LP required to protect bacteria from lipid peroxidation upon exposure to antibiotic stress and in vivo infection

3. To assess the global effects of LP and related proteins in bacterial physiology by comparative transcriptomics on mutants vs. the parental strain pairs both exposed to sublethal concentrations of antibiotics.

PhD candidates will join a vibrant, world-class team engaged in interdisciplinary studies on microbial pathogenesis using molecular biology, structural, biochemistry, and cell biology approaches, and are strongly advised to consult the following links (http://publish.uwo.ca/~mvalvano/Advice-to-grads.html) and (http://publish.uwo.ca/~mvalvano/index.html) for additional information on what to expect in the Valvano lab.

Start Date: October 2022

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