Author Proof 379 ISSN 1746-0913 Future Microbiol. (2014) 9(3), 379–397 REVIEW Background Metals such as copper, mercury and silver have been known for their ability to suppress microbial growth since antiquity. The antimicrobial properties of metals have been theorized by the Swiss chemist Nägeli [1] with the ‘oligodynamic effect’ (from the Greek: oligos = few, dynamis = force), which is a toxic effect observed at very low concentrations. Metal compounds have been exploited for a number of clinical applications, and have become an essential component of the anti-infective armamentarium [2] . The semimetal gallium (Ga) is not novel to clinical applications, as it has been extensively used as a diagnostic for the localization of malignant cells and inflammatory lesions, or as a therapeutic for the treatment of cancer, autoimmune diseases and bone resorption disorders [3–7] . The pharmacological properties of Ga(III) are attributable to its similarity with Fe(III) at the level of nuclear radius, coordi- nation chemistry and ionization potential. These features allow Ga(III) to substitute for Fe(III) in the prosthetic group of several enzymes (reviewed in [8]). Iron transport proteins, such as transferrin (Tf) and lactoferrin (Lf), are able to form complexes with Ga(III) and deliver it to the cell [9,10] . Inside the cell, Ga(III) perturbs iron metabolism since it is incorporated into essential proteins and enzymes in place of iron. Unlike iron, Ga(III) cannot be reduced under physiological conditions and, therefore, it cannot take part in redox reactions, ultimately inhibiting a number of essential functions. Several metabolic pathways, involving both Fe(III)-dependent and -independent enzymes, are targeted by Ga(III), and Ga(III)-induced metabolic distresses are dramatic in fast-growing cells, like cancer and bacterial cells [3,11–17] . Ga(III), in the form of citrate-buffered gallium nitrate [Ga(NO 3 ) 3 ], is approved by the US FDA (Ganite ® , Genta, NJ, USA) for the treatment of cancer-associated hypercalcemia. Other gallium part of 10.2217/FMB.14.3 © 2014 Future Medicine Ltd e K 3 REVIEW Promises and failures of gallium as an antibacterial agent A AS Fabrizia Minandri 1 , Carlo Bonchi 1 , Emanuela Frangipani 1 , Francesco Imperi 2 & Paolo Visca* ,1 1 Department of Sciences, University “Roma Tre”, Viale Guglielmo Marconi 446, 00146 Rome, Italy, 2 Department of Biology & Biotechnology “C. Darwin”, “Sapienza” University of Rome, Rome, Italy *Author for correspondence: Tel.: +39 06 57336347; Fax: +39 06 57336321; paolo.visca@uniroma3.it E ABSTRACT: Gallium has a long history as a diagnostic and chemotherapeutic agent. The pharmacological properties of Ga(III) rely on chemical mimicry; when Ga(III) is exogenously supplied to living cells it can replace Fe(III) within target molecules, thereby perturbing bacterial metabolism. Ga(III)-induced metabolic distresses are dramatic in fast-growing cells, like bacterial cells. Interest in the antibacterial properties of Ga(III) has been raised by the compelling need for novel drugs to combat multidrug-resistant bacteria and by the shortage of new antibiotic candidates in the pharmaceutical pipeline. Ga(III) activity has been demonstrated, both in vitro and in animal models of infections, on several bacterial pathogens, also including intracellular and bioilm-forming bacteria. Ga(III) activity is afected by iron availability and the metabolic state of the cell, being maximal in iron-poor media and in respiring cells. Synergism between Ga(III) and antibiotics holds promise as last resort therapy for infections sustained by pandrug-resistant bacteria. KEYWORDS • Acinetobacter • antibiotic resistance • anti-infectives • Burkholderia • Ganite® • iron metabolism • Mycobacterium • Pseudomonas • Staphylococcus