MIT and Boston University researchers have shown that antibiotics launch a cascade of events that produces fatal DNA damage. Image: Christine Daniloff/iMol
and other antibiotics have revolutionized medicine, turning once-deadly
diseases into easily treatable ailments. However, while antibiotics have been
in use for more than 70 years, the exact mechanism by which they kill bacteria
has remained a mystery.
a new study by Massachusetts Institute of Technology (MIT) and Boston
University (BU) researchers reveals the killing mechanism behind all three
major classes of antibiotics: The drugs produce destructive molecules that
fatally damage bacterial DNA through a long chain of cellular events.
the details of this mechanism could help scientists improve existing drugs,
according to the researchers. Few new antibiotics have been developed in the
past 40 years, and many strains of bacteria have become resistant to the drugs
could enhance the killing efficacy of our current arsenal, reduce the required
doses, or resensitize strains to existing antibiotics,” says James Collins, a
professor of biomedical engineering at BU, who collaborated with Graham Walker,
MIT professor of biology, on a study appearing in Science.
author of the paper is James Foti, a postdoctoral researcher in Walker’s laboratory.
Other authors are MIT postdoctoral researcher Babho Devadoss and Jonathan
Winkler, a recent PhD recipient in Collins’ laboratory.
In 2007, Collins showed that three classes of antibiotics—quinolones,
beta-lactams, and aminoglycosides—kill cells by producing highly destructive
molecules known as hydroxyl radicals. At the time, he and others suspected that
the radicals launch a general attack against any cell components they
react with almost everything,” Walker
says. “They’ll go after lipids, they can oxidize proteins, they can oxidize
DNA.” However, most of this damage is not fatal, the researchers found in the
proves deadly to bacteria is hydroxyl-induced damage to guanine, one of the
four nucleotide bases that constitute DNA. When this damaged guanine is
inserted into DNA, cells try to repair the damage but end up hastening their
own death. This process “doesn’t account for all of the killing, but it
accounts for a rather remarkable amount of it,” says Walker, who is an American
Cancer Society Professor.
Walker’s studies of DNA
repair enzymes led the researchers to suspect that this damaged guanine, known
as oxidized guanine, might play a role in antibiotic-mediated cell death. In
the first phase of their research, they showed that a specialized DNA-copying
enzyme called DinB—part of a cell’s system for responding to DNA damage—is very
good at utilizing the oxidized-guanine building block to synthesize DNA.
DinB not only inserts oxidized guanine opposite its correct base partner,
cytosine, on the complementary strand when DNA is being copied, but also
opposite its incorrect partner, adenine. The researchers found that, when too
many oxidized guanines had been incorporated into new DNA strands, the cell’s
unsuccessful efforts to remove these lesions resulted in death.
on these very basic DNA-repair studies, Walker and his colleagues hypothesized
that the hydroxyl radicals produced by antibiotics might be setting off the
same cascade of DNA damage. This turned out to be the case.
oxidized guanine caused by antibiotic treatment is inserted into DNA, a cellular
system designed to repair DNA kicks into action. Specialized enzymes known as
MutY and MutM make snips in the DNA to initiate repair processes that normally
help the cells deal with the presence of oxidized guanine in their DNA.
However, this repair is risky because it requires opening up the DNA double
helix, severing one of its chains while the incorrect base is replaced. If two
such repairs are undertaken in close proximity on opposite DNA strands, the DNA
suffers a double-strand break, which is usually fatal to the cell.
system, which normally should be protecting you and keeping you very accurate,
becomes your executioner,” Walker
Hung, a professor of microbiology and immunobiology at Harvard Medical
School, says that the new
study represents “the next important chapter as we’re going through 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,” says Hung, who was not part of this study.
In some cases of antibiotic-induced DNA damage, the bacterial cell is able to
save itself by repairing the double-strand break using a process called
homologous recombination. Disabling the enzymes required for homologous
recombination could increase bacteria’s sensitivity to antibiotics, the
work would suggest that proteins involved in repairing double-stranded DNA
breaks could be very interesting targets to go after as a means to affect the
killing efficacy of drugs,” Collins says.
researchers, whose work was funded by the National Institutes of Health and
Howard Hughes Medical Institute, also showed that an additional mechanism may
be involved in cell deaths caused by one of the antibiotic classes,
aminoglycosides: In cells treated with these antibiotics, oxidized guanine is
incorporated into messenger RNA, resulting in incorrect proteins that, in turn,
trigger more hydroxyl-radical production and hence more oxidized guanine. The researchers
are now working to further advance their understanding of how antibiotics kill