Host-directed therapy shows promise against antibiotic-resistant bacteria

University of Queensland researchers have found that an experimental histone deacetylase 6 inhibitor can help immune cells to restore mitochondrial fission, a cellular process that strengthens antibacterial defence without targeting bacteria directly

Researchers at the University of Queensland, Brisbane, Australia, have reported that alternative therapies designed to help the body’s immune system to fight bacteria have shown promise as a potential response to the global threat of antibiotic resistance.

The team has found that, when the body comes under attack from bacterial infection, immune cells can activate a cellular process called mitochondrial fission to help kill invading pathogens. Mitochondrial fission is the process by which mitochondria, the energy-generating structures inside cells, split into smaller units. This reorganisation helps cells to respond to stress, including infection, and appears to play an important part in antibacterial immunity.

“Some bacteria have evolved strategies to stop activation of the mitochondrial fission process, to allow the invading pathogens to survive and the infection to persist,” said Dr. James Curson, from the University of Queensland’s Institute for Molecular Bioscience.

The researchers found that an experimental treatment known as a histone deacetylase 6 (HDAC6) inhibitor could reactivate mitochondrial fission in immune cells and strengthen their capacity to fight invading bacteria. HDAC6, and inhibitors of this enzyme, have attracted research interest because of their effects on cellular stress responses, protein regulation and immune function.

“Our research found an experimental treatment called an HDAC6 inhibitor can re-activate the mitochondrial fission process in immune cells to fight invading bacteria,” said Curson.

“This treatment works by modifying the body’s immune response to support mitochondrial fission, to enable it to fight bacteria without targeting bacteria directly, like antibiotics,” he added.

The approach belongs to a class of treatments known as host-directed therapies (HDTs) which aim to stimulate or redirect the patient’s own immune response rather than attack bacteria themselves. This distinction is important because conventional antibiotics place selective pressure on bacteria, which can encourage resistant strains to emerge and spread. Host-directed therapies could offer a complementary strategy, particularly in infections where standard antibiotics have become less effective.

“Agents called host-directed therapies 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,” Curson said.

The research, which has taken more than a decade to complete, found that mitochondrial fission enhanced antibacterial responses in mammalian cells and animal models. The team reported that infection with Escherichia coli (E. coli) induced mitochondrial fission and helped to activate intracellular energy reserves. This process promoted the accumulation of antimicrobial lipid droplets which are fat-rich structures within cells that can contribute to host defence against infection.

“Specifically, we demonstrated the E. coli infection induces mitochondrial fission,” said Curson.

“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,” he added.

Antimicrobial resistance – which includes antibiotic resistance – has been identified by the World Health Organization as one of the leading global public health threats. The problem is expected to become more severe in the coming years as bacteria continue to evolve resistance to existing medicines and as the development of novel antibiotics has struggled to keep pace with clinical need.

Professor Matt Sweet, also from the University of Queensland’s Institute for Molecular Bioscience, said that ‘superbugs’ – bacteria resistant to multiple antibiotics – were very difficult to treat. He said novel approaches such as host-directed therapies were urgently required to help combat these infections.

“Antibiotic resistance leaves us vulnerable but our research shows HDTs could achieve positive outcomes,” said Sweet.

“These findings could lead to the development of novel HDTs to fight antibiotic-resistant bacterial infections, including for life-threatening conditions like sepsis,” he said.

Mitochondria are best known for their role in energy generation across the body’s cells, but they also have important immune-related functions. The latest findings suggest that their capacity to change shape and divide during infection may be more than a stress response. It may also form part of the body’s active antibacterial defence system.

“Until now, it has been unclear whether mitochondrial fission is beneficial for fighting infections and, if so, what mechanisms are involved,” said Sweet.

“Our paper revealed mitochondrial fission enhances antibacterial responses, and that we can harness this knowledge to fight bacterial infections in experimental systems,” he concluded.

For further reading please visit: 10.1126/sciimmunol.aed2623