Wednesday, June 8, 2011

Persisters induced by antibiotics- Old wine in new bottle?

Persisters are considered to be a preformed subpopulation in a bacterial culture which are not induced by antibiotics. However, Dorr et al. (2009) reported an inducible mechanism of persister formation mediated by SOS response. They found that ciprofloxacin treatment killed a majority of the population except for a small fraction of persisters. Those persisters were not a pre-formed subpopulation, but were induced by antibiotic treatment, a finding contrary to previous views. They noticed that an increase in ciprofloxacin concentration from 0.02 µg/ml to 0.5 µg/ml increased the average SOS induction and reduced the number of persister cells (Fig.2., Dorr et al. 2009). It was suggested that the bacterial persistence in the presence of ciprofloxacin was dependent on a functional SOS response. However, since all cells exposed to ciprofloxacin could induce SOS, but only a fraction became persisters, it was suggested that a specific high or low level of SOS induction was required for persister formation (Dorr et al. 2009).

However, it can be noticed that, when the ciprofloxacin concentration was increased from 0.5 µg/ml to 1 or 2 µg/ml, the persister fraction also increased with increase in SOS induction (Fig.2., Dorr et al. 2009). Increase in the number of survivors following exposure to high concentrations of quinolones has already been reported. It can be observed with a variety of quinolones at different incubation temperatures (Malik et al. 2009). Paradoxical effect of ciprofloxacin (quinolone) and oxacillin (β-lactam antibiotics) has been demonstrated by Udekwu et al. (2009) also.

Even though quinolones induce an SOS response, the SOS-DNA repair system may not play any role in protecting the bacteria from damage or cause the death of bacteria (Lewin et al. 1989). SOS induction upon treatment with quinolones may not have any effects on bacterial survival (Lewin et al. 1989). Similarly, SOS response may not be required for the paradoxical survival of bacterial cells at high quinolone concentration (Malik et al. 2009).

Dorr et al. (2009) also noticed that bacterial cultures pretreated with a low concentration of ciprofloxacin produced more persisters when incubated with higher ciprofloxacin concentrations. Based on these findings, the authors concluded that persisters are formed upon ciprofloxacin treatment rather than performing. However, the finding is not at all surprising or new. It is already reported that sub-inhibitory ciprofloxacin can induce adaptive resistance (Gould et al. 1990; Brazas et al. 2007) and that subinhibitory concentrations alter the expression of many chaperones and heat shock proteins (Brazas et al. 2007). Adaptive resistance has been reported with other antibiotics and biocides also.

Thus, Dorr et al. (2009) failed to correlate the paradoxical effect and inducible persister formation by ciprofloxacin. Even though the authors were noticing the paradoxical effect of ciprofloxacin, they failed to report it. Paradoxical effect could have been more evident, had the authors used still higher concentrations of ciprofloxacin. There is an ideal concentration of quinolone where survivors are minimal. Concentrations above or below this critical level may generate more survivors in vitro and induce an SOS response. However, the induction of SOS may not be responsible for the survival of these persisters. Similarly, adaptive resistance induced by subinhibitory concentrations of ciprofloxacin (an already known phenomenon) is made into a new topic by using the term persisters.

Next- Can treatment with bacteriostatic drugs result in persister formation?

Dorr et al. (2009). SOS response induces persistence to fluoroquinolones in Escherichia coli. PLoS Genet 5(12), e1000760.
Malik et al. (2009). Lon protease is essential for paradoxical survival of Escherichia coli exposed to high concentrations of quinolone. Antimicrob Agents Chemother 53(7), 3103-5.
Udekwu et al. (2009). Functional relationship between bacterial cell density and the efficacy of antibiotics. J Antimicrob Chemother 63(4), 745-57.
Lewin et al. (1989). 4-quinolones and the SOS response. J Med Microbiol 29(2), 139-44.
Gould et al. 1990. Concentration-dependent bacterial killing, adaptive resistance and post-antibiotic effect of ciprofloxacin alone and in combination with gentamicin. Drugs Exp. Clin. Res. 16:621-628.
Brazas et al. 2007. Role of Lon, an ATP-dependent protease homolog, in resistance of Pseudomonas aeruginosa to ciprofloxacin. Antimicrob Agents Chemother, 51(12): 4276-4283.

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