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Although neither antibiotics nor the compound "C10" when used alone can kill antibiotic-resistant persister bacterial cells, pairing C10 with antibiotics proves effective, according to Dae-Hyuk Kweon, of Sungkyunkwan University, South Korea, and his collaborators.
"We found that [C10] woke up the dormant persister cells," he says, rendering them sensitive to antibiotics. Details appear in the November 2011 Antimicrobial Agents and Chemotherapy (55:5666-5675).
"This is the first report of a compound that synergizes with antibiotics to kill persister cells," says Kim Lewis of Northeastern University in Boston, Mass. "The study seems solid." Whether C10 plus antibiotic can sterilize a stationary state culture has yet to be answered, he adds. "Persisters make up only 0.0001% of cells in an exponentially [growing] population, but rise to 1% in a stationary culture. Inability of antibiotics to eradicate stationary or biofilm populations is largely responsible for the relapsing nature of chronic infections." This study by Kweon and his collaborators is "an important step towards developing an effective sterilizing therapeutic," making it "highly significant."
In seeking a chemical compound that might prove effective against persister cells, the Korean researchers chose 6,800 from a set of 200,000 chemicals, based on their structures and physicochemical properties. They tested members of this group by combining each of these individual compounds with one or the other of the antibiotics ampicillin and norfloxacin, looking for those compound pairs that killed all targeted persister cells. The researchers then screened out those compounds that killed persister cells in the absence of either antibiotic. C10 was singled out from a final set of eight compounds that killed persister cells when combined with norfloxacin. Its chemical name is 3-(4-(4- methoxyphenyl)piperazin-1-yl)piperidin- 4-yl biphenyl-4-carboxylate.
Once combined with norfloxacin, C10 boosts the efficiency of bacterial cell killing from 99.99 to 100%, Kweon says. That increase is much larger than it sounds, he says. For instance, a difference of 0.01% among 108 cells is 10,000 cells. In terms of dormant survivor cells within a culture flask that might be resistant to antibiotics, that number of cells per milliliter is plenty to replenish the population soon after antibiotics are withdrawn.
While no less pernicious, persistence differs from antibiotic resistance. Thus, persister cells are genetically identical to antibioticsusceptible cells, whereas resistant cells carry mutations or distinctive genes conferring resistance. Bacterial persisters, which withstand antibiotics by remaining in a dormant state, are likely critical in forming biofilms and for supporting chronic and recurrent infections. Moreover, the potential for antibiotic resistance to emerge during treatments is proportional to the number of persister cells present in a bacterial population, according to Kweon and his collaborators. "Thus, a strategy to remove these persisters is a critical outstanding issue both for prevention of secondary infection and for prevention of resistant cell emergence," they note.
"This selective killing of persisters in combination with antibiotics provides new options for studying the mechanism of persistence, and for preventing emergence of resistant cells," Kweon says. "If C10 binds and inhibits enzyme X, then we can infer that enzyme X plays a critical role in persistence."
David C. Holzman
David C. Holzman is the Microbe Journal Highlights Editor.
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