The "antibiotic era", characterized by the overuse and misuse of antibiotics, over the last half-century has culminated in the present critical "era of resistance". The treatment of bacterial infections is challenging because of a decline in the current arsenal of useful antibiotics and the slow rate of new drug development. The discovery of a new gene (mcr-1) in 2015, which enables bacteria to be highly resistant to polymyxins (such as colistin), the last line of antibiotic defence left, heralds a new level of concern as this gene is susceptible to horizontal gene transfer, with alarming potential to be spread between different bacterial populations, suggesting that the progression from "extensive drug resistance" to "pan-drug resistance" may be inevitable. Clearly there is a need for the development of novel classes of anti-bacterial agents capable of killing bacteria through mechanisms that are different to those of the known classes of antibiotics. 1,10-phenanthroline (phen) is a heterocyclic organic compound which exerts in vitro antimicrobial activity against a broad-spectrum of bacteria. The antimicrobial activity of phen can be significantly modulated by modifying its structure. The development of metal-phen complexes offers the medicinal chemist an opportunity to expand such structural diversity by controlling the geometry and varying the oxidation states of the metal centre, with the inclusion of appropriate auxiliary ligands in the structure, offering the opportunity to target different biochemical pathways in bacteria. In this review, we summarize what is currently known about the antibacterial capability of metal-phen complexes and their mechanisms of action.

Dinuclear Cu2+ and Mn 2+ bis-phenanthroline octanedioate compounds exhibit rapid, unprecedented nano and picomolar in vitro cytotoxicity against human-derived colorectal cancer lines (HT29, SW480 and SW620) and are less cytotoxic toward non-cancerous normal human keratinocyte cells (HaCaT). Both complexes displayed greater in vivo drug tolerance compared to cisplatin when examined using the insect Galleria mellonella. The compounds are potent generators of intracellular reactive oxygen species within HT29 cells, display avid DNA binding and induce O 2 -dependent cleavage of supercoiled pUC18 DNA. The Cu 2+ complex was found to display self-cleaving nuclease activity and a mechanism of deoxyribose C-H bond activation is proposed, based on interactions with the superoxide anion and hydrogen peroxide along with DNA cleavage observations under anaerobic conditions and with an excess of the metal chelator EDTA.

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Mycobacterium tuberculosis is the etiologic agent of tuberculosis. The demand for new chemotherapeutics with unique mechanisms of action to treat (multi)resistant strains is an urgent need. The objective of this work was to test the effect of manganese(II) and copper(II) phenanthroline/dicarboxylate complexes against M. tuberculosis. The water-soluble Mn(II) complexes, [Mn2(oda)(phen)4(H2O)2][Mn2(oda)(phen)4(oda)2]·4H2O (1) and {[Mn(3,6,9-tdda)(phen)2]·3H2O·EtOH}n (3) (odaH2 = octanedioic acid, phen = 1,10-phenanthroline, tddaH2 = 3,6,9-trioxaundecanedioic acid), and water-insoluble complexes, [Mn(ph)(phen)(H2O)2] (5), [Mn(ph)(phen)2(H2O)]·4H2O (6), [Mn2(isoph)2(phen)3]·4H2O (7), {[Mn(phen)2(H2O)2]}2(isoph)2(phen)·12H2O (8) and [Mn(tereph)(phen)2]·5H2O (9) (phH2 = phthalic acid, isophH2 = isophthalic acid, terephH2 = terephthalic acid), robustly inhibited the viability of M. tuberculosis strains, H37Rv and CDC1551. The water-soluble Cu(II) analog of (1), [Cu2(oda)(phen)4](ClO4)2·2.76H2O·EtOH (2), was significantly less effective against both strains. Whilst (3) retarded H37Rv growth much better than its soluble Cu(II) equivalent, {[Cu(3,6,9-tdda)(phen)2]·3H2O·EtOH}n (4), both were equally efficient against CDC1551. VERO and A549 mammalian cells were highly tolerant to the Mn(II) complexes, culminating in high selectivity index (SI) values. Significantly, in vivo studies using Galleria mellonella larvae indicated that the metal complexes were minimally toxic to the larvae. The Mn(II) complexes presented low MICs and high SI values (up to 1347), indicating their auspicious potential as novel antitubercular lead agents.