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High-resolution genome mapping of the antibiotic-resistant 'golden staph' hospital superbug has revealed the many mutations these dangerous bacteria use to cause untreatable infections, a study by the Doherty Institute for Infection and Immunity (Doherty Institute) has found – holding promise for future improved diagnosis and treatment for struggling patients and hospitals.

Published in eLife, this large-scale study observed nearly 400 rapidly evolving golden staph infections to see which mutations produced strains of the bacteria that evade both our immune responses and antibiotics.

Golden staph can cause potentially life-threatening blood infections that are becoming increasingly resistant to the strongest antibiotic treatment.

Study lead author University of Melbourne Doctor Stefano Giulieri, clinician-researcher and PhD candidate at the Doherty Institute, said genomics combined with computational science provided the tools to undertake a kind of detective work in reverse, catching the golden staph culprit in the cradle and observing its evolutionary tricks to outwit the immune system and antibiotics.

“Golden staph triggers severe infections in the blood that are notoriously difficult to treat – setting off an arms race with your immune system and antibiotics struggling to eliminate the rapidly mutating and changing bacteria,” Doctor Giulieri said.

“Catching subtle genetic mutations in real-time reveals golden staph’s genetic playbook, providing an opportunity to develop treatments to stop infections in their tracks and giving the immune system and antibiotics a much-needed head start.”

Joint senior author University of Melbourne Professor Tim Stinear, Laboratory Head and Senior NHMRC Research Fellow at the Doherty Institute, said the study demonstrated the potential of an emerging science called 'statistical genomics' to transform the way infectious diseases are diagnosed and treated.

“The findings present an opportunity to predict which strains might cause the most severe infections, lighting the path toward personalised clinical treatments for individual infections using bacterial genome analysis and emerging gene editing technologies.” Professor Stinear said.

The study found that during severe infections, mutations of the golden staph bacteria occurred among a small group of 'adaptive genes' that included a well-known 'master regulator' called the accessory gene regulator. The accessory gene regulator can flip golden staph between 'Jekyll and Hyde' like states that make the bacteria very difficult to kill.

Novel genes not previously described were also identified, including those affecting the processing of sugar and fat inside the bacterium to keep it alive.

“Critically, these processing genes were not previously understood to be linked to antibiotic resistance, underscoring how careful, whole genome studies of many thousands of bacteria can point to unexpected findings.” Professor Stinear said.

Joint senior author University of Melbourne Professor Ben Howden, Director of the Microbiological Diagnostic Unit (MDU) Public Health Laboratory at the Doherty Institute said the study revealed that mutations of the genetic code were not the only way golden staph infections adapt and spread within our body.

“We observed golden staph ‘turning off’ genes by inserting small fragments of DNA that migrate from one region of the genome to other. Golden staph has discovered a way to use these ‘selfish genes’ to its advantage.” Professor Howden said.

The study between the Howden and Stinear research groups was undertaken in collaboration with the CAMERA2 study group at the Menzies School of Health Research and the Big Data Institute at the University of Oxford.

Funding: NHMRC
Peer review: https://doi.org/10.7554/eLife.77195