Potential new target in fight against antibiotic-resistant superbug discovered
Researchers at the University of Cambridge have discovered how an antibiotic-resistant superbug exploits oxygen-limited conditions in the lungs of patients with severe respiratory disease to thrive.
It is hoped the discovery could lead to new ways to target the Pseudomonas aeruginosa bacterium, which is responsible for six per cent of healthcare associated infections in NHS patients and has a widespread resistance to many antibiotics.
Infection by P. aeruginosa is a major cause of death in patients with Cystic Fibrosis.
The research shows that an infection pathway in P. aeruginosa is activated when the bug encounters low-oxygen conditions.
"This is particularly important because the bug is strongly associated with infections in patients with severe respiratory disease; most famously patients with cystic fibrosis – many of whom eventually succumb to P. aeruginosa infections," said lead investigator Dr Martin Welch, from the University of Cambridge Department of Biochemistry.
"Counter-intuitively, the lung tissue of such patients is oxygen-limited, so this could trigger the pathway," he noted.
P. aeruginosa infection in the lungs promotes an inflammatory response that destroys lung tissue. When the bug encounters low oxygen conditions, a mechanism called the Type III Secretion System (T3SS) is triggered.
The T3SS resembles a molecular-scale 'hypodermic syringe' which is thought to inject toxins directly from the bacterium into the host cell, where they subvert its function and lead to cell death.
The team identified a metabolic 'switch' regulating T3SS activity, called the glyoxylate shunt, which is activated when oxygen is sparse.
When this 'switch' is turned on an enzyme called isocitrate lyase (ICL) is expressed, leading to activation of the T3SS. In the absence of ICL, the T3SS is not turned on in low-oxygen conditions.
"The mechanism by which ICL impacts on the T3SS involves a previously unrecognised regulatory pathway. Crucially we found that this regulatory pathway also affected the formation of antibiotic-resistant biofilms by P. aeruginosa. This is important because biofilm formation is known to play an important role in the pathology of cystic fibrosis-associated infections," Dr Welch explained.
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