Tripathi K , Kulshreshtha S. Metalloantibiotics-I. Biomed Pharmacol J 2008;1(1).

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Manuscript received on :February 12, 2008
Manuscript accepted on :April 04, 2008
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618

Kishu Tripathi^¹ and Shobha Kulshreshtha^²

^¹Surya College of Pharmacy, Lucknow.

^²Head, Department of Pharmacology, SN Medical College, Agra.

Abstract

Metal ions after forming complexes with an antibiotics alters the antimicrorial activity of an antibiotics alone.

Keywords

Metal ions; antibiotics

Introduction 

A strong affinity of tetracycline and oxy- and chlortetracycline for metallic ions was reported by Albert (3, 8) who observed the formation of drug-metal complexes of 1:1 and, as the pH is raised, of 2:1. The cations tested (in the order of decreasing stability of the drug-metal complexes) were: Fe++, Al+++, Cu2+ , Ni++, Fe++,Co2+, Zn2+, and Mn2+. The iron complexes of the tetracyclines are red, the Cu2+, and Ni2+ complexes are green, and the Al3+,Co2+,Zn2+, and Mn2+ complexes are yellow. In contrast,Oxford (77) was not able to obtain colored complexes of chlortetracycline with Zn2+or Mn2+but did observe stable yellow complexes with Cu2+, Ni2+, Co2+ Mg2+, Ca2+ and Sr4+.The tetracycline structure contains numerous sites at which chelation with metallic ions might occur. Perhaps the most important sites lie along the system marked by atoms 1 through 7which consists essentially of two 1,3 diketones with two of the keto groups in the enol form.Such monoenols in 1,3 diketones chelate with metallic ions very readily to form six-membered. In each ring, the two atoms that bind the metallic ion are oxygen atoms (23):

Scheme 1 Click here to View scheme

Scheme 2 Click here to View scheme

The tetracycline compounds have been described as uncouplers (21) and inhibitors (107)of oxidative phosphorylation and inhibitors of respiration (91, 99, 106), fatty acid oxidation, arginine catabolism (55), nitro reduction (92, 93, 94), and adaptive enzyme formation (15).The possibility that metallic ions might enhance the activity of the drugs was during the series of growth tests described above. Moderate enhancement was observed with low concentrations of Mn2+ or with high concentrations of Fe+ with P. aeruginosa (112,113). Previously, chlortetracycline had been found to be enhanced by similarly low concentrations of Mn+| in its antibiotic effect against C. cucullus (65).The resistant strains tested to date include a strain of M. pyogenes whose average minimum inhibitory concentration of tetracycline and oxy- and chlortetracycline is 120 pg per ml and a strain of Penicillium notatum which requires 750 pug per ml of the drugs for suppression of growth. Fe2+ and Mg2+ are active with the bacterium and Fe+H with the fungus. 8-HYDROXYQUINOLINE Molecular Structure and Affinity for Metallic Cations Of seven isomeric mono-hydroxyquinolines, only 8-hydroxyquinoline (oxine) can chelate metallic ions (9, 90): Sexton (97) observed that the Cu2+, Ni2+ , Cd++, and Ag+compounds of 8-hydroxyquinoline are as fungistatic as oxine itself; and Manten et al. (67)reported that neither Zn+, Cu++, Mn2+ nor

Scheme 3 Click here to View scheme

Mo2+-suppresses the toxicity of oxine toward Aspergillus. Other investigators reported that Cations Cu2+ and Fe2+ enhance antifungal activity (10)and that conalbumen suppresses the antibacterial action of 8-hydroxyquinoline (36). Gram positive bacteria are more susceptible to oxine than are gram negative species and trace amounts of Co2+ excess amounts of Fe++ suppress the activity of 8-hydroxyquinoline against the former organisms whereas Fe2+, Zn2+ or Cu2+ suppress the toxicity of oxine towards the latter bacteria. Furthermore, with Micrococcus pyogenes, an increase in the concentration of 8-hydroxyquinoline results in a paradoxical decrease in toxicity. Subsequent studies revealed that small concentrations of Fe2+ Cu2+, or Cd2+ are required for toxicity towards gram positive species and that a 2:1 oxine-Fe- molar ratio is maximally toxic.

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