A naturally occurring predatory bacterium is able to work with the immune system to clear multi-drug resistant Shigella infections, according to a study involving academics at The University of Nottingham.
The research, published in the journal Current Biology, has shown for the first time that the predatory bacteria Bdellovibrio bacteriovorus can be used successfully as an injected anti-bacterial therapy and represents an important step in the fight against drug-resistant infections or ‘superbugs’.
Shigella infection is responsible for more than 160 million illnesses and more than one million deaths every year – and is a common cause of ‘travellers’ diarrhoea’. Cases of drug-resistant Shigella are also on the rise as, although the diarrhoea usually clears up without treatment, antibiotics are often used even in mild cases to stop the symptoms faster.
Resistance to antibiotics has prompted the team of researchers from Nottingham, in collaboration with colleagues at Imperial College London, to look to the natural environment for creative solutions to this problem.
To investigate Bdellovibrio’s ability to control drug resistant Gram-negative infections, researchers injected zebrafish larvae with a lethal dose of Shigella flexneri strain M90T which is resistant to both streptomycin and carbenicillin antibiotics.
Bdellovibrio was then injected into the larvae’s infection site, and a decrease in the number of Shigella was seen. In the absence of Bdellovibrio, zebrafish were unable to control the replication of Shigella and the levels of the bacteria rose.
Professor Liz Sockett, of the University of Nottingham’s School of Life Sciences, a predatory bacteria expert, joined forces for the project with Dr Serge Mostowy of Imperial College London’s MRC Centre for Molecular Bacteriology, an expert on bacterial infection models in zebrafish.
Professor Sockett said: “This has been a truly groundbreaking collaboration and the combinations of different fluorescently-coloured bacteria and white blood cells shows therapeutic Bdellovibrio in action inside the translucent living zebrafish.
“The predatory action of the Bdellovibrio breaks the Shigella-pathogen cells and this stimulates the white blood cells; redoubling their ‘efforts’ against the pathogen and leading to increased survival of the zebrafish ‘patients’.”
Bdellovibrio can invade and kill a range of Gram-negative bacteria, such as E. coli and Salmonella, in the natural environment. Previous research has shown that it can reduce pathogen numbers in the stomach of chickens when taken as an oral therapy, but there is growing need to develop therapies to target infections in wounds and organs. Successful use of Bdellovibrio highlight its potential uses in tackling a range of drug-resistant Gram-negative bacterial infections that can develop in hospital patients. Remarkably, Bdellovibrio is also able to reduce pathogen load in immunocompromised zebrafish larvae that have been depleted of white blood cells. However, survival is significantly greater in immune-competent zebrafish, showing that Bdellovibrio’s maximum therapeutic benefit comes from its ability to work cooperatively with the host’s own immune system.
Wellcome Research Career Development Fellow Dr Serge Mostowy, co-lead author from Imperial College London said: “This study really shows what a unique and interesting bacteria Bdellovibrio is as it presents this amazing natural synergy with the immune system and persists just long enough to kill prey bacteria before being naturally cleared. It’s an important milestone in research into the use of a living antibiotic that could be used in animals and humans.”
Dr Michael Chew, Science Portfolio Advisor at Wellcome said: “It may be unusual to use a bacterium to get rid of another, but in the light of the looming threat from drug resistant infections the potential of beneficial bacteria/animal interactions should not be overlooked. We are increasingly relying on last line antibiotics and this innovative study demonstrates how predation could be an important additional tool to drugs in the fight against resistance.”
This research was funded by Wellcome, the Leverhulme Trust, the Lister Institute of Preventive Medicine, the Medical Research Council, U.S. Army Research Office and the Defense Advanced Research Projects Agency.
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Notes to editors: The University of Nottingham has 43,000 students and is ‘the nearest Britain has to a truly global university, with a “distinct” approach to internationalisation, which rests on those full-scale campuses in China and Malaysia, as well as a large presence in its home city.’ (Times Good University Guide 2016). It is also one of the most popular universities in the UK among graduate employers and was named University of the Year for Graduate Employment in the 2017 The Times and The Sunday Times Good University Guide. It is ranked in the world’s top 75 by the QS World University Rankings 2015/16, and 8th in the UK for research power according to the Research Excellence Framework 2014. It has been voted the world’s greenest campus for four years running, according to Greenmetrics Ranking of World Universities.
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