Antibiotics Kill Bacteria By Damaging Their DNA
It is astonishing that we have been using antibiotics like penicillin for over 70 years, yet we did not know the exact mechanism by which they kill bacteria, until now.
The researchers say understanding this mechanism could help improve existing drugs, a most welcome piece of news as few new antibiotics have been developed in the last 40 years, and many strains of bacteria have developed resistance to the ones currently available.
Co-author Dr James J Collins, Professor of Biomedical Engineering and William F. Warren Distinguished Professor at Boston University, told the media:
"One could enhance the killing efficacy of our current arsenal, reduce the required doses or resensitize strains to existing antibiotics."
In 2007, Collins discovered that three types of antibiotic, the quinolones, the beta-lactams and the aminoglycosides, all kill cells by producing hydroxyl radicals, highly destructive molecules that appear to attack just about any cell components that stand in their way: they attack lipids, they oxidize proteins, and they oxidize DNA.
But in this latest study, they found that most of this damage is not fatal.
The deadly blow is hydroxyl-induced damage to guanine, one of the four nucleotides or building blocks of DNA.
The researchers found that when they inserted damaged (ie oxidized) guanine into DNA, the cells try to repair the damage, but instead this speeds up their own death.
Corresponding author Dr Graham Walker, MIT Professor of Biology, said the mechanism isn't behind all the killing, but it appears to be responsible for a major part of it.
The team began investigating the guanine damage aspect as a result of Walker's studies of DNA repair enzymes. They had a hunch oxidized guanine played a key role in cell death.
First they showed that DinB, a DNA-copying enzyme that springs into action when DNA is damaged, uses oxidized guanine.
But, DinB makes a gross error: not only does it place the damaged guanine correctly opposite its base partner cytosine on the copy, it also puts it incorrectly opposite adenine.
Once too many damaged guanines are inserted into the new DNA strands, the cell tries to remove these errors, but this only serves to hasten its own death.
The team then showed that this also happens with antibiotics: their hydroxyl radicals trigger the same cascade of DNA damage.
Once oxidized guanine caused by antibiotic treatment is inserted into DNA, it triggers a cellular mechanism that repairs DNA.
The mechanism relies on MutY and MutM, specialized enzymes that make cuts in the DNA to trigger actions that deal with the fact the DNA contains oxidized guanine.
But these repairs are not without risk: they have to unravel the DNA double helix, and cut one of the chains, to replace the incorrect base. This is not a problem unless two such repairs happen close to each other: then the DNA suffers what is known as a "double-strand break", which usually kills the cell.
Walker said the system that should normally be "protecting you and keeping you very accurate", then "becomes your executioner".
Dr Deborah Hung is a professor of microbiology and immunobiology at Harvard Medical School and was not involved with the study. She said with studies like this, we are undergoing a "renaissance of understanding how antibiotics work":
"We used to think we knew, and now we've realized that all our simple assumptions were wrong, and it's much more complex."
The researchers also have a suggestion for how this knowledge might be used to make existing drugs more effective at killing bacteria.
They said in some cases, the bacterial cell can save itself when its DNA is damaged by repairing the double-strand break, a process known as "homologous recombination".
Blocking homologous recombination, for instance by disabling the enzymes required, could make the bacteria more sensitive to the antibiotic, they suggest.
Funds from the the National Institutes of Health and Howard Hughes Medical Institute helped pay for the study.
Written by Catharine Paddock PhD
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