CP251 may find application in the treatment of external
infections such as those associated with wounds. Iron is an essential element for the growth of virtually all bacteria and fungi. Thus, limiting the amount of available iron should in principle inhibit microbial growth (Bezkorovainy, 1980; Lewin, 1984). Most microorganisms have developed efficient methods of absorbing iron from the environment and many microorganisms check details secrete siderophores in order to scavenge iron (Hider & Kong, 2010). Such methods of uptake can be circumvented by the introduction of high-affinity iron-selective chelating agents. However, the affinity of these agents for iron must be extraordinarily high, enabling them to compete efficiently with siderophores. One problem with the concept of using iron chelators as antimicrobial agents is that they
may interfere with the immunodefence centred on endothelial cells and phagocytes. The presence of a low level of relatively accessible iron is essential for the formation of hydroxyl radicals during the respiratory burst of such cells (Baggiolini, 1984; Halliwell & Gutteridge, 1984). Thus iron-chelating strategies are not likely to be successful with systemic application of chelators. However topical application of chelators will not suffer from such a disadvantage and may find cosmetic application, use in wound healing and in the treatment of nail infections. 8-Hydroxyquinoline and related compounds were first demonstrated to possess antimicrobial properties over 50 years ago (Albert et al., 1947; Lowe & Phillips, 1962). More recently, the hexadentate
chelator N,N′-ethylenebis[2-(2-hydroxyphenyl)-glycine] screening assay has been found to exhibit moderate-to-good activity against isolates of pathogenic bacteria and fungi, whereas EDTA and diethylene-triamine pentaacetic acid (DTPA) revealed weaker activity (Bergan et al., 2001). Chew et al. (1985) reported that EDTA possessed strong activity against Gram-positive bacteria but was much less effective against Gram-negative bacteria. Indeed, DTPA was more growth inhibitory than EDTA Terminal deoxynucleotidyl transferase against the Gram-negative bacteria. The antimicrobial activity of iron(III) chelators has been investigated by a number of groups over the past decade, but the majority of this effort has been directed to bidentate chelators (Jain et al., 2005; Banin et al., 2006; Gademann et al., 2007; Zhang et al., 2007), which generally possess a lower affinity for iron than their hexadentate analogues (Liu & Hider, 2002). The chelating moiety, 3-hydroxypyridin-4-one, by virtue of possessing a high affinity and selectivity for iron(III), has been considered for several therapeutic applications (Liu & Hider, 2002). Its bidentate form, deferiprone, is an effective orally active iron chelator and has been widely used for the treatment of iron overload associated with β-thalassaemia (Balfour & Foster, 1999; Maggio, 2007; Porter, 2009).