Zincophore metal binding sites: from solution equilibria to metal transport in human pathogens

The assimilation of metal nutrients from the host environment is an important factor for the onset and progression of infectious diseases. Zn(II) ions, in particular, are crucial for the virulence and survival of both pathogen and human cells, being indispensable for the expression and function of many enzymes. Interestingly, the Zn(II) uptake mechanism is one of the major differences in the metabolism of human and pathogen cells, thus it represents a promising drug-target for specific and selective treatments [1]. Pathogens compete with the host organism in order to acquire zinc and meet their physiological metal nutrient demands. An efficient zinc recruitment is therefore achieved by means of specialized zinc-binding proteins and molecular systems which capture the metal ion from the host environment forming stable complexes [2, 3]. A deep knowledge of the properties, structure and action mechanisms of these extracytoplasmic zinc chelators (zincophores) can be a powerful tool to design new therapeutic strategies against the antibiotic and/or antifungal resistance [4]. As a first step, it is essential to obtain information about thermodynamics and coordination chemistry of the involved systems, in order to point out the most effective metal binding sites and to elucidate the dynamics behind the metal transfer. Indeed, a relatively high metal binding affinity is crucial to ensure the acquisition process in an environment rich of competitive systems and thermodynamic studies may help clarifying this aspect. An outstanding example is given by the characterization of the zinc-binding sites of the periplasmic protein ZinT, expressed by Escherichia coli and Salmonella enterica [5]. References: [1] Capdevila, D.A.; Edmonds, K.A.; Giedroc, D.P., Metallochaperones and metalloregulation in bacteria. Essays Biochem., 2017, 61 (2), 177-200. [2] Hennigar, S.R.; McClung, J.P., Nutritional Immunity: Starving Pathogens of Trace Minerals. Am. J. Lifestyle Med., 2016, 10 (3), 170-173. [3] Morey, J.R.; Kehl-Fie, T.E., Bioinformatic Mapping of Opine-Like Zincophore Biosynthesis in Bacteria. mSystems, 2020, 5 (4), e00554-00520. [4] Battistoni, A.; Ammendola, S.; Chiancone, E.; Ilari, A., A novel antimicrobial approach based on the inhibition of zinc uptake in Salmonella enterica. Future Med. Chem., 2017, 9 (9), 899-910. [5] Bellotti, D.; Rowińska-Żyrek, M.; Remelli, M., Novel insights into the metal binding ability of ZinT periplasmic protein from Escherichia coli and Salmonella enterica. Dalton Trans., 2020, 49 (27), 9393-9403.