Group B Streptococcus kills more newborn babies than any other infectious agent, and the bacterium survives the body's immune attack by breaking down the amino acid arginine to resist zinc poisoning. The problem is that up to 25% of adults carry GBS harmlessly, but during birth the bacterium can turn deadly, invading the brain, lungs, blood, and other organs. The immune system normally fights GBS by flooding it with toxic levels of zinc, but the pathogen has evolved ways to withstand this metal stress. Researchers have discovered that deleting genes involved in arginine catabolism—a core pathway present in many bacterial pathogens—dramatically weakens GBS's ability to survive zinc intoxication. This is fundamental science: the team aims to understand exactly how arginine breakdown protects the bacterium, how the pathway is regulated, and whether an existing FDA-approved drug can disrupt it. If successful, the work could lead to therapies that boost the body's own antimicrobial defences against GBS without relying on antibiotics, offering a strategy that sidesteps growing antimicrobial resistance. Because the arginine pathway is highly conserved across bacteria, the findings might also apply to other important pathogens.
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Group B Streptococcus (GBS) is the leading cause of death in new-born babies and life-long debilitating illness in those it does not kill. The bacterium usually lives in the adult human body but is easily passed from mother to baby during birth, where it seizes the opportunity to infect. Up to 25% of us carry GBS as part of our normal microbiome but the factors affecting its transition to an opportunistic pathogen are not well understood. GBS causes severe disease in the elderly and those with co-morbidities, but it is also an important pathogen of animals and fish; infections cause significant losses to milk production and aquaculture industries. The pathogen can spread throughout the body and invade multiple cell, tissue and organ types (e.g. brain, lungs, blood, kidneys, bladder and skin), demonstrating its ability to survive in diverse environments within the body. GBS does this by resisting the antimicrobial actions of the human immune system. One way that our bodies fight off invading pathogens is by subjecting them to toxic levels of certain reactive metals such as Zinc (Zn). Zn is an essential element for all kingdoms of life, but this highly reactive metal is toxic when levels become mis-managed in biological systems. This occurs during host-pathogen interactions between white blood cells and GBS. In studying how GBS responds to metals, we recently identified several new biological processes that are essential for resisting Zn stress, including some 'core pathways' that are present in most bacterial pathogens. This has led us to identify a set of novel genes which may explain why GBS is able to subvert certain antimicrobial actions of the human immune system and represent exciting new lines of investigation. Using gene-knockout technology, deletion of several genes involved in arginine catabolism drastically altered GBS’s ability to survive during intoxication by free Zn ions. We predict these capabilities can be targeted, ultimately, with treatment strategies that enhance the potency of the human body's 'usual' antimicrobial responses as a killing mechanism that is independent from antibiotic treatment, representing a promising alternative therapy that could be addressed using existing drugs. We are well suited for this study because: -We were first to identify a link between arginine catabolism and Zn resistance in bacteria. -We deciphered the ‘transcriptome’ and ‘resistome’ of GBS during Zn intoxication. -We developed and extensively used advanced molecular techniques for studying GBS, required for this project. This proposal will test the hypothesis that arginine catabolism is pivotal to resisting Zn intoxication in GBS. Genes and compounds that control this pathway are central to the bacterium's intrinsic resistance to elevated intracellular Zn and confer a survival advantage. Our objectives are to: Investigate how arginine catabolic pathways confer survival to GBS when exposed to high Zn conditions Decipher the regulation of arginine catabolism in GBS and identify a regulatory feed-in for Zn Repurpose an FDA-approved drug to target arginine catabolism to disrupt Zn resistance in GBS The approaches will incorporate cutting-edge molecular techniques and produce highly trained research scientists. The outcomes will be fundamental knowledge in the microbiology discipline with potential to feed future development of therapeutic approaches targeting GBS that circumvent antimicrobial resistance. Given the pathways to be studied are highly conserved in bacteria, the outcomes may also contribute to novel therapeutic strategies that target other important pathogens.
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