Biologists
at the University of California, San Diego have developed a
revolutionary new method for identifying and characterizing antibiotics,
an advance that could lead to the discovery of new antibiotics to treat
antibiotic resistant bacteria.
The researchers, who published their
findings in this week’s early online edition of the journal Proceedings
of the National Academy of Sciences, made their discovery by developing a
way to perform the equivalent of an autopsy on bacterial cells.
“This will provide a powerful new tool
for identifying compounds that kill bacteria and determining how they
work,” said Joseph Pogliano, a professor of biology at UC San Diego who
headed the research team. “Some bacteria have evolved resistance to
every known class of antibiotic and, when these multi-drug resistant
bacteria cause an infection, they are nearly impossible to treat. There
is an urgent need for new antibiotics capable of treating infections
caused by antibiotic resistant bacteria.”
The Centers for Disease Control and
Prevention issued an alarming report in March that antibiotic-resistant
strains of Carbapenem-Resistant Enterobacteriaceae, or CRE, had been
found to cause infections in patients in nearly 200 hospitals in the
United States alone. Because no antibiotics on the market are effective
at treating these infections, about one-half of patients die from CRE
infections. These outbreaks are difficult to contain, and in a 2011
outbreak of Klebsiella pneumonia at the US National Institutes of Health
Clinical Center, the bacteria spread despite strict infection control
procedures and was detected in drains and medical devices that had been
subject to standard decontamination protocols.
“We are finally running out of the
miracle drugs,” said Pogliano, who detailed the history: The antibiotic
penicillin was first discovered in the late 1920s, and received
widespread clinical use in the 1940s. However, bacteria quickly evolved
resistance to penicillin, so new and better versions were developed.
Since that time, a continuous race has been fought to identify new
antibiotics in order to stay one step ahead of the evolving resistance.
In the 2011 outbreak of Klebsiella, the bacteria evolved resistance even
to colistin, a drug of last resort because of its severe side effects.
Over the last 25 years, the number of
new antibiotics entering the clinic has drastically declined. At the
same time, bacteria have continued to evolve resistance to all of the
currently available drugs, creating the current critical situation. One
of the main problems in identifying new antibiotics and bringing them to
market is a lack of understanding how the molecules work.
“It’s easy to identify thousands of
molecules capable of killing bacteria,” explained Kit Pogliano, a
professor of biology and a co-author of the paper. “The hard part is
picking out the winners from the losers, and choosing molecules that are
the best candidates for drug development. One key piece of information
needed for this choice is knowledge of how the drug works, but this is
traditionally difficult information to obtain, usually requiring months
of intensive work. We’ve applied 21st century methods that within just
two hours provide this information, allowing more rapid prioritization
of new molecules. This will open up the discovery pipeline, allowing us
to more rapidly identify new molecules with potential to enter the
clinic for treatment of multi-drug-resistant pathogens.”
One key to this new approach was the
combination of microscopy and quantitative biology tools. “We had to
develop all of the cell biology and quantitative biology methods for
generating the data ourselves and that required a lot of work, but now
that we have the method working, it is very exciting,” said Poochit
Nonejuie, a graduate student in the Division of Biological Sciences and
another co-author. “My chemistry colleagues can give me a new molecule
in the morning, and by the afternoon I can tell them the likely cellular
pathways that they target. It’s mind blowing how powerful the
technology is.
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