Each year, the World Health Organization recognizes March 24 as World Tuberculosis (TB) Day – a day to educate the public about the continued impact of TB around the world. The date marks the day in 1882 when Dr. Robert Koch announced that he had discovered the bacterium that causes TB, Mycobacterium tuberculosis (Mtb), which opened up research towards diagnosing and curing the disease.
The TB epidemic is still very prevalent today. One-third of the world’s population is exposed to TB, which kills nearly two million people annually with over 10 million new infections taking place each year. In 2022 alone, 10.6 million people fell ill with TB and 1.3 million people died (https://www.who.int/campaigns/world-tb-day/2024). But since the year 2000, 75 million lives have been saved because of global efforts to end TB.
From the UBC Department of Microbiology and Immunology, researchers in the Yossef Av-Gay, Lindsay Eltis, and Jim Sun labs share how their research contributes to the fight against Tuberculosis.
Av-Gay Lab
In the Av-Gay lab, their primary research focus is Tuberculosis (TB) pathogenesis. Over the years, the lab has covered multiple aspects of Mtb physiology and pathogenesis, and have now expanded into three main research areas: (i) Signal transduction in mycobacteria and between Mtb and the host macrophage, (ii) Novel approaches for drug discovery focusing on the intracellular lifestyle of Mtb and (iii) Nitric oxide as anti-infective agent.
Henok Sahile, a Postdoctral Fellow in the Av-Gay lab, specifically works on discovering novel antimicrobial drugs, with a major emphasis on developing Host-Directed Therapies (HDT) for combating tuberculosis (TB).
“My particular interest is to repurpose the commonly used antiallergen drugs, specifically antihistamine drugs, for use against TB in combination with other antibiotics. This research hypothesis stems from my initial findings indicating that an FDA-approved drug, functioning by inhibiting the histamine receptor 1 (HR1) on macrophages—the primary defense cells in Mtb infection—can restrict the growth and replication of intracellular Mtb without directly targeting the bacteria. Together, with other colleagues, I also conducted further investigations to confirm HR1 as a valid drug target for HDT in TB.”
By utilizing various medicinal chemistry tools, Henok’s goal is to refine the chemical structure of the identified drug, aiming to enhance its potency and minimize off-target effects that contribute to adverse reactions.
“The development of an HDT with a novel mode of action, when used alongside existing antibiotics, is expected to revolutionize the existing TB treatment approaches by reducing the excessively prolonged treatment duration and boosting the efficacy of existing drugs against multidrug-resistant bacteria.”
Read more about the Av-Gay lab: https://av-gaylab.med.ubc.ca
Eltis Lab
The overall objective of research in the Eltis lab is to characterize key pathways and enzymes involved in the catabolism of aromatic compounds and steroids in Mycobacterium and Rhodococcus. Specifically, the lab seeks to understand: 1) the pathways and enzymes involved in the catabolism of ligning-derived aromatics, 2) how we can harness catabolic and oleaginous abilities of Rhodococcus to create biocatalysts, and 3) how steroid catabolism is essential to the pathogenesis of Mycobacterium tuberculosis (Mtb).
Adriana Ibtisam (MSc student) and Julia Kleetz (Postdoctoral Fellow) in the Eltis lab share their specific research on Mtb.
Adriana works on using fluorescent reporter genes to characterize the spatiotemporal dynamics of cholesterol catabolism in Mycobacteria (including Mtb). Since Mtb relies on cholesterol from host cells as a source of energy during pathogenesis, Adriana’s project seeks to characterize when and where during infection the bacteria is breaking down cholesterol.
“On a broader level, I would love if my project could go on to facilitate the development of new chemo-therapeutics for treating tuberculosis,” says Adriana.
Julia currently works on the biosynthesis of compounds called oxazolones in Mtb and other bacteria. These oxazolones are a novel group of lipids only recently described to be produced in bacteria.
“In Mtb, several lipids have roles in pathogenicity and persistence, making the discovery of new lipids and how they are produced a very interesting target for research,” shares Julia. “Currently, my work is focused on the enzymes involved in the biosynthesis of oxazolones, but understanding their function and their potential role in pathogenicity will be my next focus.”
Read more about this topic: https://doi.org/10.1016/j.jbc.2023.104924
Read more about the Eltis lab: https://www.eltislab.com
Sun Lab
Jim Sun, one of our newest Assistant Professors, and his lab study how bacterial pathogens evade our immune system using advanced imaging, flow cytometry, multi-omics and functional genomics approaches. Their research provides unique promise to develop host-directed therapeutic approaches to combating emerging pandemic-level threats.
With a lab focus on tuberculosis, immunity, and drug discovery, researchers Yichu Liang (PhD Candidate) and Peng (Allen) Xu (Postdoctoral Fellow), share their work from the Sun lab in the fight against TB.
Peng shares that over the past several decades, scientists have been working on developing novel antibiotics to target Mtb. But that over the past 40 years, only two clinical drugs, called Bedaquiline and Pretomanid, have been approved for TB treatment and the resistance of these anti-TB drugs accumulates day by day.
“According to Global TB Report 2023, in 2022, the estimated proportion of people with TB who had Multidrug-resistant or Rifampicin-resistant TB was 3.3% among new cases and 17% among those previously treated,” says Peng.
Peng, whose current research focusses on TB Host-Directed Therapies (HDT) says that the obvious advantage of HDT is it may work better on resistant strains and can avoid resulting new resistance.
“Recently, we completed a human genome-wide CRISPR knockout screen to identify critical human genes involved in maturation of Mtb-containing phagosome,” says Peng. “Phagosome maturation is crucial for innate immune response to eliminate Mtb when Mtb initiates infection through macrophage. As Mtb produces a bunch of virulence factors to disrupt phagosome maturation to promote its intracellular survival and replication, it is rational to enhance phagosome maturation to fight back. So, phagosome maturation is a promising target for TB HDT.
In this screen, we discover two group of genes that when deleted may promote Mtb-phagosomematuration, but have not been previously linked to phagosome maturation. Both groups of genes may be novel regulators of phagosome maturation and are potential targets for TB HDT. The future plans of this project are to (1) validate these hits using genetic and/or pharmacological methods (e.g. CRISPR knockout and overexpression, inhibitors, and agonists) and (2) determine the molecular mechanisms of how these genes/pathways regulate phagosome maturation in the context of Mtb infection as well as (3) discover inhibitors to target these genes/proteins and try to transform them into clinical treatment of TB.”
Yichu also works in the same realm on the development of new host-directed drugs against TB. The target he focusses on is a human phosphatase named PPM1A, which they found to be hijacked by Mtb to weaken macrophages and promote bacterial survival during infection.
“We developed new inhibitors of PPM1A, namely a compound called SMIP-30, which can successfully be used to treat infected macrophages and make them better at killing Mtb,” shares Yichu. “SMIP-30 was also able to increase the efficacy of the TB antibiotic rifampicin in mice, showing promise as an adjunctive drug as well. So far, we know that SMIP-30 can increase autophagy in macrophages, but I'm working on characterizing more possible cellular mechanisms as well as screening new generations of optimized derivative compounds.”
Read more about this topic in Cell Chemical Biology (https://pubmed.ncbi.nlm.nih.gov/35320734/) and STAR Protocols (https://pubmed.ncbi.nlm.nih.gov/35880128/).
Read more about the Sun lab: https://www.thesunlab.ca