Antimicrobials: Killing Persisters While They Sleep

RESEARCH HIGHLIGHTS

ANTIMICROBIALS Killing persisters while they sleep Bacterial persisters are a certain metabolites can enhance of mannitol enhanced gentamicin subpopulation of dormant cells the killing of both Gram-negative killing of persister cells by more than that have been implicated in a and Gram-positive persisters by two orders of magnitude. Similarly, it may be possible range of chronic and recurrent aminoglycosides. in mice that were implanted with to eradicate infections through their ability Aminoglycoside uptake into the catheters which had been colonized bacterial to survive antibiotic treatments. bacterium is energy dependent, by a uropathogenic E. coli strain, Although most cellular processes are leading the authors to investigate administration of mannitol together persisters in a completely shut down in persisters, whether metabolic stimulation with gentamicin reduced the viability clinical setting translation still occurs, albeit at a enhances the killing of persister of biofilm bacteria on the catheter by stimulating reduced rate, making the use of cells by increasing the uptake of by more than an order of magnitude. their underlying aminoglycoside antibiotics (which these antibiotics. They found that Finally, the authors tested whether metabolic activity target the ribosome) an attractive the addition of glucose, mannitol, metabolite addition enhanced option. However, aminoglycosides fructose or pyruvate increased the aminoglycoside killing of Gram- concurrently have only weak activity against this killing of isolated Escherichia coli positive bacteria; whereas mannitol, with antibiotic subpopulation of cells. Writing persisters by gentamicin, kanamycin glucose and pyruvate had no effect, treatment. in Nature, Collins and colleagues and streptomycin by more than three the addition of fructose enhanced now show that the addition of orders of magnitude. The effect was killing of Staphylococcus aureus specific to aminoglycosides, as none persisters by more than two orders of the metabolites that were screened of magnitude. enhanced killing by either quinolones These findings indicate that it or β-lactam antibiotics, which target may be possible to eradicate bacterial DNA replication and cell division, persisters in a clinical setting respectively. The authors observed by stimulating their underlying that the addition of these metabolites metabolic activity concurrently enhanced gentamicin uptake and with antibiotic treatment. that killing was reduced by blocking Andrew Jermy this uptake using the proton-motive

force inhibitor carbonyl cyanide ORIGINAL RESEARCH PAPER Allison, K. R., m-chlorophenyl hydrazone (CCCP). Brynildsen, M. P. & Collins, J. J. Metabolite-enabled In an E. coli biofilm model, the eradication of bacterial persisters by aminoglycosides. Nature 473, 216–220 (2011) authors found that the addition