Antibacterial effects of metal complexes

The use of silver nitrate and colloidal silver in wounds dates from the mid-nineteenth century and the term oligodynamic was applied to the antimicrobial action of heavy metals diluted in water [9]. Over the years, attempts to put silver in contact with wounds produced a number of electrolytic methods [9] as well as use of solutions of silver nitrate, in this case as late as 1965 [16]. However, the imbalance of sodium, potassium and chloride caused by silver nitrate in these cases was unsatisfactory due to the number of resulting side effects. These include in some cases methemoglobinemia from reduction of nitrate to nitrite. In 1968, a complex (AgSD) formed from a sulfonamide and silver was introduced in attempts to combine the oligodynamic action of the heavy metal with the antibacterial effect of the sulfonamide [17]. The insoluble product, which is used as a 1% cream, has suitable properties and excellent wide spectrum antibacterial activity, and is used worldwide for burn prophylaxis and other infectious skin conditions [9]. Side effects are few, the major one being leukopenia. The properties and mode of action of AgSD have been reviewed [9,18]. 

Azelaic acid (AA), 1,9-nonanedioic acid or heptane-1,7-dicarboxylic acid, is used in manifold application areas. AA is offered in the pharmaceutical field for the treatment of acne and rosacea due to its antibacterial effect [1,2]. However, AA is much more widely applied as a monomer for the production of polymers such as alkyd resins, polyamides, and impact-proof polyesters or for the synthesis of plasticizers, lubricants, lithium complex greases, corrosion inhibitors, dielectric fluids, heat-transfer fluids, metal to glass fluxes, emulsion breakers, waxes, tobacco sheet plasticizers, hot-melt coatings and adhesives, water-soluble coating resins, hydraulic fluids, fungicides, insecticides, and so on [3-7]. 

Work has been performed in which the quaternary pyridinium functionality was attached to 7-oxanorbornene-5,6-exo-dicarboximide-functionalised monomers which were subsequently polymerised using a Grubbs catalyst (Grubbs catalysts are a series of transition metal carbene complexes used as catalysts for olefin metathesis). The polymer series, a-f, and quaternised polymer, a , (Figure 9.1 and Table 9.1) was designed to study the effect of the hydrophobic alkyl substituent on the antibacterial and haemolytic activities of polymers using dimethylformamide (DMF) as the solvent. 

Before leaving the subject of the mechanism of metal-ion transport across membranes, a cautionary result and a by-product of these investigations might be reported. Hall has found that the antibiotic monamycin forms complexes in solution with K+, Rb+, and Cs+, but not with Na+ or Li+. However, it seems that their antibacterial action is due to their lytic effects on cell membranes rather than to any ion-transporting properties they may possess. The metal-ion selectivity of nonactin and valino-mycin has been put to use in the design of potassium-selective membrane electrodes. These contain the antibiotics as components of the membrane, and can be used to estimate K+ in the presence of Na+, for example in human serum. 

The dissociation of silver may not in some cases be a prerequisite for activity silver uracil complexes did not penetrate cells and the in vitro antibacterial action was attributed to membrane effects [25]. A survey of the in vitro antimicrobial effects of a series of metal sulfanilamides also appointed silver and gold salts as the most active, the gold sulfadiazene being as active as the silver complex [26]. The chemistry and microbiology of these species has been summarized [27]. 

The ubiquitous chelates of 1,10-phenanthroline were studied some time ago for their antiviral activity [17]. The inhibitory effect of various chelates on the multiplication of influenza virus (Melbourne strain) in chick chorioallantoic membrane in vitro was studied, and the most effective complex was shown to be the [Ru(acac) (3,5,6,8-Me4-l,10-phen)2] cation, which inhibited multiplication at concentrations of 6 X 10 M(—log M = 6.2). Other chelate complexes were active at concentrations of 10 to 10 M. A structure—activity study of metal chelates showed, however, that for a given chelate ligand, more labile complexes such as those of Cd or Cu were more active than their inert counterparts, the order for doubly-charged (2+) chelates being Cd(II) > Cu(II) > Zn(II) > Mn(II) > Fe(II) > Co(II) > Ni(II) > Ru(II) [18]. This correlation coincided with that found for some antibacterial effects (Chapter 9). Further studies showed that the virostatic activity may be manifested by either direct inactivation of the virus (possibly through dissociation of the more labile chelates) or by direct action on the host cell (for inert complexes). The latter effect is indicated by the fact that the trend in virostatic activity is similar to that in antitumour activity [19] (see also Chapter 6) and the fact that, of the various 1,10-phenanthrolines studied, the tetramethyl derivatives most easily penetrate cells [20]. 

The tetracyclines Form an important group of antibiotics. The activity appears to result from their ability to chelate metal ions since the extent of antibacterial activity parallels the ability to form stable chelates. The metal in question appears to be magnesium or calcium since the addition of large amounts of magnesium can inhibit the antibiotic effects. In addition, it is known that in blood plasma the tetracyclines exist as calcium and magnesium complexes.,JS... 

The use of organotransition metal chemistry to effect the synthesis of complex molecules under exceptionally mild conditions has been applied to the synthesis of the sensitive p-lactam nucleus by a number of research groups. Through the use of this methodology the synthesis of the typical C-3-acylamino-substituted compounds as well as novel structures with unexpected antibacterial activity has been achieved. 

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