Alternative therapies that aid the body's immune system to fight bacteria have shown promise in addressing the global threat of antibiotic resistance.
University of Queensland researchers have found when under attack, the body's immune cells activate a cellular process called 'mitochondrial fission' to kill invading bacteria.
Dr James Curson , from UQ's Institute for Molecular Bioscience , said mitochondrial fission was a critical process in which mitochondria within cells split into smaller units to support the body's response to stresses, including infections.
"Some bacteria have evolved strategies to stop activation of the mitochondrial fission process – allowing the invading pathogens to survive, and the infection to persist," Dr Curson said.
"Our research found an experimental treatment called an HDAC6 inhibitor can re-activate the mitochondrial fission process in immune cells to fight invading bacteria.
"This treatment works by modifying the body's immune response to support mitochondrial fission, enabling it to fight bacteria without targeting bacteria directly, like antibiotics.
"Agents called host-directed therapies (HDTs) that activate the host immune response to fight infections are a promising alternative to antibiotics, which could contribute to addressing the global burden of antibiotic-resistant bacteria," Dr Curson said.
The research, more than a decade in the making, found mitochondrial fission enhances the body's antibacterial response to infections in mammalian cells and animal models.
"Specifically, we demonstrated the E. coli infection induces mitochondrial fission," Dr Curson said.
"The triggering of this cellular process then activates the body's intracellular energy reserves to accumulate antimicrobial lipid droplets – defence mechanisms that help fight off infections."
Antimicrobial resistance, which includes resistance to antibiotics, has been named a top global public health threat by the World Health Organization, and is expected to worsen in coming years.
Professor Matt Sweet , of UQ's Institute for Molecular Bioscience , said bacteria resistant to multiple antibiotics, often called 'superbugs', are very difficult to treat and new approaches like HDTs are urgently needed to combat these infections.
"Antibiotic resistance leaves us vulnerable, but our research shows HDTs could achieve positive outcomes," Professor Sweet said.
"These findings could lead to the development of new HDTs to fight antibiotic-resistant bacterial infections, including for life-threatening conditions like sepsis."
Mitochondria are important for the generation of energy in all cells but also have additional immune-related functions.
"Until now, it has been unclear whether mitochondrial fission is beneficial for fighting infections and, if so, what mechanisms are involved," Professor Sweet said.
"Our paper revealed mitochondrial fission enhances antibacterial responses, and that we can harness this knowledge to fight bacterial infections in experimental systems."
Read the research in the journal Science Immunology.
Collaboration and acknowledgements:
This project involved key collaborations with the research groups of Professor Steven Zuryn and Professor Rob Parton at The University of Queensland, as well as a number of international researchers including Dr. Ronan Kapetanovic (National Research Institute for Agriculture, Food and the Environment, France), Professor Patrick Matthias (Friedrich Miescher Institute for Biomedical Research, Switzerland) and Professor Albert Pol (August Pi i Sunyer Biomedical Research Institute, Spain).
The researchers wish to acknowledge the Institute for Molecular Bioscience's Advanced Microscopy Platform and the Microscopy Australia Research Facility at the Centre for Microscopy and Microanalysis at The University of Queensland.
