Antimycobacterial activity of rhodamine 3,4-HPO iron chelators against Mycobacterium avium: analysis of the contribution of functional groups and of chelator's combination with ethambutol
Rhodamine-labelled 3-hydroxy-4-pyridinone (3,4-HPO) chelators exhibit antimycobacterial activity, related but not limited to their iron binding capacity. We previously found that bacterial growth inhibition observed for chelators with ethyl substituents on the amino groups of the xanthene ring of rhodamine and a thiourea linkage between rhodamine and the chelating unit (MRH7 and MRB7) was different from that of compounds with methyl substituents and an amide linkage (MRH8 and MRB8). In this work we evaluated the antimycobacterial activity of two new chelators (MRH10 and MRB9) expressly designed to allow: (a) the direct comparison of the influence of the functional groups per se and (b) identification of the finest combination to achieve a higher biological activity. The activity of the chelators was assessed, as previously, by measuring their effect against M. avium. In this study we also report the antimycobacterial effect of MRH7, which proved to be the best performer of all four chelators, in combination with ethambutol, which is one of the antibiotics currently in use to treat mycobacterial infections. The results are indicative that a combination of 3,4-HPO iron chelators with an antibiotic is a promising strategy to fight M. avium infections. The current results are relevant for the choice of the best chelator in our set of compounds and also for the design of novel molecular architectures to target cellular membranes.