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Applying a Trojan Horse Strategy to Ruthenium Complexes in the Pursuit of Novel Antibacterial Agents

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Laurent Quentin, Batchelor Lucinda K., Dyson Paul J.,
Project Modulation of the site specificity of binding of metal-based drugs to chromatin
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Original article (peer-reviewed)

Journal Organometallics
Volume (Issue) 37(6)
Page(s) 915 - 923
Title of proceedings Organometallics
DOI 10.1021/acs.organomet.7b00885

Abstract

Since the discovery of penicillin in 1928,1 a tremendous number of antimicrobial drugs have been developed targeting bacteria (antibacterial), fungi (antifungal), viruses (antiviral), and parasites (antiparasitic). As a consequence, many common yet fatal illnesses such as pneumonia and tuberculosis have become less deadly. Infections were, for a time, no longer an ever present risk and the dangers linked to surgery or childbirth were drastically reduced. However, due to the intensive worldwide use of antibiotics, especially in agriculture, bacteria and other pathogens have evolved to overcome the effect of these drugs. Antimicrobial resistance (AMR) is becoming increasingly problematic as the discovery of new antibiotic formats has slowed, and is now an issue of global importance.2−5 With infections and infectious diseases remaining one of the major causes of death worldwide,6 and the emergence of antibacterial resistance, the development of novel classes of antibacterial drugs is of the utmost importance. Ruthenium(III) and ruthenium(II) drugs are prominent families of anticancer agents, developed in the quest to overcome platinum-based resistance.7 At the forefront are NAMI-A,8 KP1019,9 and NKP-1339,10 showing promising results in preclinical and phase I and I/II clinical trials. Ruthenium(II)−arene complexes such as RAPTA ([Ru(η6- arene)X (PTA)], PTA = 1,3,5-triaza-7-phosphaadamantane)11 activity against different strains of bacteria.16 Ruthenium(II)− arene complexes represent an interesting platform that can be easily structurally modified, and several clinical drugs such as kinase inhibitor staurosporine,17 glutathione-S-transferase in- hibitor ethacrynic acid,18 antifungal agents,19 or antibacterial quinolones20,21 have been coupled to them, either to augment their anticancer activity or to have dual-functioning drug candidates, being both antibacterial and anticancer agents.20,21 Coupling these two therapeutic effects is desirable in the clinics where patients treated for cancer often show weakened ability to fight infections.22 Iron is an essential element for almost all organisms (animals, plants, and micro-organisms), being involved in electron transport and metabolic processes from photosynthesis to DNA biosynthesis.23 This involvement in so many biological reactions makes it a vital element for the survival of living organisms. While animals can source iron from food, plants and microorganisms need to obtain it from their surrounding environment. The most common strategy is the use of ferric ion chelators as solubilizing agents.24 This is achieved through the secretion of siderophores (literally “iron carriers”). These low molecular weight compounds (<1000 Da) possess an extremely high affinity for the Fe3+ ion.25 Siderophores are secreted by bacteria in response to an iron restriction to scavenge any Fe3+ that can be found in the surrounding 2 or RAED (([Ru(η6-arene)(en)Cl]+, en = ethylenediamine)12 environment. Siderophores usually form hexadentate octahe- show a wide range of promising anticancer properties.13−15 Interestingly, RAPTA-C, arene = p-cymene, has also been investigated as a potential antimicrobial agent and displayed
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