Reply to “The Dual Personality of Iron Chelators: Growth Inhibitors or Promoters?”

REPLY

In their letter, Visca et al. have shown that P. aeruginosa can use deferiprone as an iron “carrier,” which in turn promotes bacterial growth in a low-iron M9 minimal medium (1). Since our initial publication, we have also observed that the presence of deferiprone (and some other iron chelators) at sub-MICs can promote the growth of clinical isolates of Acinetobacter baumannii in M9 minimal medium (our unpublished results). However, while these data are in agreement with the results published by de Léséleuc et al. with respect to deferiprone and A. baumannii (2), in our hands, they were also strain and chelator dependent. For example, we did not observe growth promotion with VK28 and A. baumannii (unpublished results). We agree with Visca et al. that the consequences of growth promoted by iron chelators at sub-MIC levels in minimal media need to be considered before clinical application. However, it is unclear how relevant these findings would be in vivo if a high-enough concentration of a chelator can be achieved (≥1× MIC). With systemic applications, these concentrations are not possible because of toxicity concerns, but for wound infections, a topical, nonsystemic application could be considered and was also highlighted in a recent review (3).

It should also be noted that our original intent was to investigate the utility of iron chelators in combination with the current standard of care with respect to war wound infections. The current standard of care to treat devastating extremity wounds suffered by U.S. military personnel includes broad-spectrum antibiotic treatment and often negative-pressure wound therapy. Other groups have shown that iron chelators in combination with antibiotics against several bacterial species in vitro resulted in a significant increase in bacterial killing, due in some cases to biofilm dispersal (4–7). Our approach, while similar, relied on more recently developed iron chelators (i.e., VK28 and Apo6619) (8), and we actively sought out the synergy with various conventional antibiotics. This approach has led to the discovery that, while some iron chelators have a high MIC alone against common, nosocomial bacteria (8), they also have a synergistic effect with specific antibiotics against A. baumannii (A. C. Jacobs, M. G. Thompson, B. W. Corey, and D. V. Zurawski, unpublished data) and other bacteria (D. V. Zurawski, U.S. patent application PCT/US12/23377). Some of these data have been presented at recent meetings (9, 10).

In light of many studies and years of research regarding iron chelators as antimicrobials, including both the failures and successes in vitro and in vivo, it is clear that many factors will contribute to their potential utility. While caution should be employed, we should still consider the prospect of using iron chelators in specific clinical settings. Clearly the choice of chelator, bacterial susceptibility, the application (i.e., systemic versus nonsystemic), and the potential of synergy, whether it be with conventional antibiotics or with other antibacterial therapies, will all need to be considered in order to optimize therapeutic potential. Given the unrelenting emergence of multidrug-resistant bacteria and the growing lack of treatment options, further research is still warranted.