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The Elliot Lab: Driving the production of cryptic antibiotics in Streptomyces

Written by Tori Marko, Research Laboratory Technician, Surette Lab

Dr. Marie Elliot’s research team at McMaster University studies multicellular development and gene regulation in Streptomyces bacteria to understand the metabolic capabilities of these organisms, including how to induce metabolite production for the discovery of antibiotics.

 

Lsr2 knockdown promotes antibiotic production and leads to increased killing of Methicillin-resistant Staphylococcus aureus (MRSA) and Vancomycin-Resistant Enterococci (VRE). Images courtesy of Dr. Hindra (unpublished).

Antibiotic resistance is rapidly emerging as a major global crisis, prompting the World Health Organization to declare this phenomenon as one of the top 10 global health threats of 2019. Researchers within the Michael G. DeGroote Institute for Infectious Disease Research (IIDR) and David Braley Centre for Antibiotic Discovery (DBCAD) at McMaster University aim to address this problem from many angles, including the study of bacteria that are naturally equipped to kill other bacteria. Dr. Marie Elliot, Professor and incoming Chair of the Department of Biology, studies a group of bacteria called Streptomyces that have a complex multicellular lifestyle and an extraordinary ability to make interesting natural products. Broadly, the Elliot lab focuses on Streptomyces gene regulation and how this influences development and specialized metabolite production.

In their recent BioRxiv preprint titled “Silencing cryptic specialized metabolism in Streptomyces by the nucleoid-associated protein Lsr2″, the Elliot lab characterized the Lsr2 protein, which binds DNA to repress gene expression. Intriguingly, they found that many Lsr2-repressed genes are involved in specialized metabolite production. This included metabolites that are considered “cryptic”, where the genes required for their production are normally silent (not expressed) and their products are unknown. Postdoctoral Fellow Dr. Hindra and Undergraduate Co-op student Meghan Pepler showed that by reducing Lsr2 activity, Streptomyces bacteria can be coaxed into producing more antibiotics to increase killing of other bacteria including the dangerous pathogens methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE). With this new key to unlocking specialized metabolite production, they are continuing to search for novel antibiotics in libraries of “wild” Streptomyces isolates. In the future, Dr. Hindra hopes to further extend his experiments to other types of bacteria.

Xiafei Zhang is a PhD student who is delving deeper into the mechanism underlying Lsr2-mediated repression of genes required for antibiotic production. Together with Dr. Elliot and Dr. Hindra, Fei published a review in Current Opinion in Microbiology highlighting clever ways to trick microbes into producing molecules that are otherwise not detectable under laboratory conditions. MSc student Emma Mulholland was recently awarded a Canada Graduate Scholarship to study gene regulation in Streptomyces, with a focus on novel regulatory elements governing specialized metabolism. She is examining Streptomyces strains lacking proteins that degrade RNAs to understand how these enzymes function, which RNAs they target, and how they influence specialized metabolism.

The Elliot Lab. Top row, left to right: Dr. Marie Elliot, Dr. Hindra, Xiafei Zhang. Bottom row, left to right: Emma Mulholland, Matthew Zambri, Evan Shepherdson, Meghan Pepler.

The Elliot Lab made headlines in 2017 with their widely received eLife paper, in which former PhD student Dr. Stephanie Jones discovered a novel mode of Streptomyces development called “exploration”. More recently, current MSc student Matthew Zambri helped Dr. Jones demonstrate a link between exploration and iron limitation, showing that bacterial compounds can modulate microbial community dynamics by altering environmental nutrient profiles. Matt is currently working to understand if and how different nutrients inhibit or trigger this fascinating behaviour.

Lastly, MSc student Evan Shepherdson studies Streptomyces exploration from a different angle, focusing on the effects of glycerol. His preliminary work shows that adding glycerol to exploring Streptomyces increases killing of other bacteria; he is currently working to further characterize this phenotype. Evan, who holds a Canada Graduate Scholarship and will subsequently receive an Ontario Graduate Scholarship, emphasizes that studying Streptomyces exploration may also lead to the discovery of new antibiotics, as this understudied mode of development appears to promote the synthesis of unique sets of metabolites.

This year Elliot Lab trainees showcased their exciting projects at the Great Lakes Natural Product Symposium in Kingston, ON, and the McMaster Faculty of Health Sciences Research Plenary. As Dr. Elliot is currently the President of the Canadian Society of Microbiologists, her lab will naturally be attending the 2019 CSM Annual Conference at Sherbrooke, QC, where they will give oral and poster presentations on their projects. Be sure to look for Elliot Lab trainees at the upcoming IIDR Trainee Day 2019 on Friday, October 4th to hear more about the amazing research taking place in this lab.

 

About the Author

 

 

Victoria Marko, Research Laboratory Technician, MSc

Tori completed her MSc in Dr. Lori Burrows‘ lab in the Department of Biochemistry and Biomedical Sciences, where she studied the regulation of motility and virulence in Pseudomonas aeruginosa. She is currently a technician in Dr. Michael Surette’s lab, where she isolates bacteria from healthy human gut samples with the goal of discovering novel natural products. In her free time, she enjoys making agar art, playing piano, painting, and Instagramming her cats, Porter and Stout.

 

Author:

Christy Groves