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Science: Study Reveals New Survival Strategy for Bacteria Exposed to Antibiotics
Researchers have uncovered a new way that some bacteria survive when under siege by antibiotics.
This survival mechanism is fundamentally different from other known bacterial strategies. Understanding it may be useful for designing drugs that target hard-to-treat bacterial strains such as drug-resistant tuberculosis (TB), an increasingly urgent public health problem. The study is based on Mycobacterium smegmatis—a cousin of the microbe that causes TB—and its response to the TB drug isoniazid.
The research, by Yuichi Wakamoto of the University of Tokyo and Neeraj Dhar of the Swiss Federal Institute of Technology in Lausanne and colleagues, appears in the 4 January issue of Science.
Researchers observed as early as 1944 that antibiotics are less effective against cell populations that aren't proliferating through cell division. More recently, experiments have shown that some bacteria survive exposure to antibiotics thanks to a population of non-dividing "persister cells" that are present in the bacterial population even before the antibiotic treatment begins.
"This concept has been widely accepted as a general explanation for bacterial persistence," Wakamoto said, "despite very limited experimental support."
Timelapse microscopy of M. smegmatis, exposed to the antibiotic isoniazid, shows the cells slowing their rates of growth and division after one dose. After the antibiotic is removed, one of the cells resumes rapid growth and division.
[Video courtesy of Yuichi Wakamoto, Neeraj Dhar, John D. McKinney]
Wakamoto and colleagues now report that non-dividing persister cells are not responsible for the survival of M. smegmatis exposed to isoniazid. In fact, cell survival is not related to growth rate at all. Instead, random pulses of a bacterial enzyme called KatG make it possible for some cells to survive antibiotic treatment.
"Our Science paper provides clear experimental proof that other mechanisms of persistence also exist," said Dhar. "Our findings necessitate the re-examination of the mechanisms of persistence at the single-cell level in other bacteria, including Mycobacterium tuberculosis, which causes TB in humans."
The researchers studied single M. smegmatis cells in microfluidic cultures, treated with isoniazid. The drug is a "pro-drug" that does not become active until it is administered and interacts with certain compounds in the bacterial cell. In the case of M. smegmatis, it's KatG that activates isoniazid.
Individual bacterial cells fates were not correlated with their growth rates, but rather with their production of KatG. Each cell produced KatG in random pulses that determined the cell's chances of survival.
The researchers conclude that in certain cells, there were periods in between pulses when enzyme conversion of the pro-drug was barely possible. Thus a few cells probably avoided being killed by the activated antibiotic.
"At present we can only speculate as to whether the same or similar mechanisms exist in other bacterial species, although we think this is likely," said Wakamoto.
3 January 2013