A new theory of how low doses of antibioitics create antibiotic resistance

Feb 11, 2010 – usatoday.com

E.coli bacteria is seen under a microscope.

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By Centers for Disease Control

Exposure to low levels of antibiotics increases mutations in E. coli and Staphylococcus bacteria hundreds of time more than normal, making the creation of drug-resistance strains more likely, says a paper in today’s edition of the journal Molecular Cell.

This finding adds to concerns about antibiotic resistance brought on by poor prescriptions practices among doctors, patients who don’t take all their medicine and even low doses of antibiotics given to help animals grow faster.

The researchers found that while low levels of antibiotics may not be enough to kill off the bacteria, they still stress them. That stress causes them to produce free radicals, says James Collins, a biomedical engineer at Boston University and one of the paper’s authors.

Those free radicals are produced by oxidation, a process that’s known to damage cells. In the case of bacteria, the free radicals damage the bacteria’s DNA, causing some of the affected bugs to mutate.

Two and a half years ago Collins’ group began looking at how bacteria respond to antibiotics. It was then that they discovered that antibiotics can stimulate the pathways that create free radicals in bacteria.

A year ago they started considering what other implications their discovery might have.

“We wondered whether sub-lethal levels still produce free radicals. We know the cells wouldn’t die, but we know that free radicals can damage DNA, and that increases mutenigenesis,” he says.

And that’s exactly what they found. Basically, if the antibiotic dose isn’t high enough to kill every bacteria in sight, “you could be creating a zoo with a wide range of mutations,” he says.

The  finding is important “within the context of our understanding — or lack of understanding — of how bacteria become resistant to antibiotics,” says Deborah Hung, a molecular biologist at Massachusetts General Hospital, who wrote an accompanying Perspective piece on the article.

The  truth is that no one really knows exactly how bacteria become resistant to antibiotics, says Hung. So knowing that low levels of antibiotics might potentially increase the random chance that bacteria might mutate into resistant forms could have important implications for medicine.

By Elizabeth Weise

DNAWellnessinfo.com Resource:  http://content.usatoday.com/communities/sciencefair/post/2010/02/a-new-theory-of-how-low-doses-of-antibioitics-create-antibiotic-resistance/1

New antibiotics could come from a DNA binding compound that kills bacteria in 2 minutes

June 8, 2009

Synthetic DNA binding compound has proved surprisingly effective at binding to the DNA of bacteria and killing all the bacteria it touched within two minutes. The DNA binding properties of the compound were first discovered in the Department of Chemistry at the University of Warwick by Professor Mike Hannon and Professor Alison Rodger (Professor Mike Hannon is now at the University of Birmingham). However the strength of its antibiotic powers have now made it a compound of high interest for University of Warwick researchers working on the development of novel antibiotics.

Dr Adair Richards from the University of Warwick said:

“This research will assist the design of new compounds that can attack bacteria in a highly effective way which gets around the methods bacteria have developed to resist our current antibacterial drugs. As this antibiotic compound operates by targeting DNA, it should avoid all current resistance mechanisms of multi-resistant bacteria such as MRSA.”

The compound [Fe2L3]4+ is an iron triple helicate with three organic strands wrapped around two iron centres to give a helix which looks cylindrical in shape and neatly fits within the major groove of a DNA helix. It is about the same size as the parts of a protein that recognise and bind with particular sequences of DNA. The high positive charge of the compound enhances its ability to bind to DNA which is negatively charged.

When the iron-helicate binds to the major groove of DNA it coils the DNA so that it is no longer available to bind to anything else and is not able to drive biological or chemical processes. Initially the researchers focused on the application of this useful property for targeting the DNA of cancer cells as it could bind to, coil up and shut down the cancer cell’s DNA either killing the cell or stopping it replicate. However the team quickly realised that it might also be a very clever way of targeting drug-resistant bacteria.

New research at the University of Warwick, led by Dr Adair Richards and Dr Albert Bolhuis, has now found that the [Fe2L3]4+ does indeed have a powerful effect on bacteria. When introduced to two test bacteria Bacillus subtilis and E. coli they found that it quickly bound to the bacteria’s DNA and killed virtually every cell within two minutes of being introduced – though the concentration required for this is high.

Professor Alison Rodger, Professor of Biophysical Chemistry at the University of Warwick, said:

“We were surprised at how quickly this compound killed bacteria and these results make this compound a key lead compound for researchers working on the development of novel antibiotics to target drug resistant bacteria.”

The researchers will next try and understand how and why the compound can cross the bacteria cell wall and membranes. They plan to test a wide range of compounds to look for relatives of the iron helicate that have the same mechanism for action in collaboration with researchers around the world.Professor

Mike Hannon from the University of Birmingham said:”This research is a great example of how the Universities of Birmingham and Warwick are working together to deliver exciting new research that can impact on medicine and healthcare  – key themes of the AWM “Birmingham Science City” initiative which seeks to make the West Midlands the leading player in science and technology in the UK.”

The research has just been published in the International Journal of Antimicrobial Agents in a paper entitled Antimicrobial activity of an iron triple helicate by Dr Adair D. Richards, and Professor Alison Rodger from the University of Warwick, Professor Michael J. Hannon from the University of Birmingham and Dr Albert Bolhuis from Bath University. Issue 33 pp469-472 http://www.ijaaonline.com/article/S0924-8579(08)00577-3

For further information please contact

Adair Richards
University of Warwick on
+44 (0)24 7657 5797
adair.richards@warwick.ac.uk

or

Peter Dunn, Press and Media Relations Manager
University House,
University of Warwick, Coventry, CV4 8UW, United Kingdom
email: p.j.dunn@warwick.ac.uk
Tel: +44 (0)24 76 523708 Mobile/Cell: +44 (0)7767 655860
Twitter: @PeterJDunn

DNAWellnessInfo.com Resource:  http://www2.warwick.ac.uk/newsandevents/pressreleases/new_antibiotics_could