METALLOPORPHYRINS--NOVEL TOPICAL MICROBICIDES

Emory University, Atlanta GA

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Abstract

Metalloporphyrins (MNPs) have been shown by our work to possess potent broad spectrum antibacterial activity and to utilize a novel bacterial target. MNPs inhibit growth of N. gonorrhoeae, H. ducreyi while sparing lactobacilli and other anaerobic bacteria. Gram-negative and Gram- positive bacteria, and acid-fast bacilli are also sensitive to MNPs. MNPs were not toxic to primary human fibroblasts, several established cell lines, and experimental animals at concentrations >100 fold higher that MIC for sensitive bacteria. MNPs are antibacterial "Trojan horses" since they exploit natural, high affinity, bacterial heme transport systems as portal of entry into the cell. The STD pathogens N. gonorrhoeae and H. ducreyi possess several independent heme uptake mechanisms. The utilization of heme-containing compounds is an established virulence characteristic of a bacterial pathogen, and in the case of H. ducreyi heme is an essential metabolite since this pathogen cannot synthesize heme. Rare bacterial mutants that stop expressing heme-uptake systems and become resistant to MNPs should be less virulent or nonviable, minimizing the impact of resistance to MNPs. This proposal seeks funds to verify and expand these promising results, to explore the fundamental science underlying these discoveries, and to lay the foundation for clinical application of this drug class as topical microbicides to prevent STDs and/or HIV infection. The spectrum of activity of MNPs will be studied in vitro and in cell culture. We will identify environmental conditions that synergize/antagonize the activity of MNPs and/or affect their stability. Distribution of MNPs in the bacterial cell and analysis of MNP-resistant and/or hypersensitive mutants will be studied in order to identify MNP bacterial targets. Systematic variations of the MNP structure will provide a tool for identification of parts of MNP molecules that are important for MNP antibacterial activity. In addition, bactericidal activities of natural and synthetic porphyrins with and without the central metal ion will be investigated. Genetic toxicity will be tested on bacteria and lymphoma cells. Cytotoxicity against several cell lines and primary T lymphocytes will be examined. Catabolism of MNP in tissue homogenates will be followed to determine whether the body is able to metabolize small amounts of MNPs that may get reabsorbed from the female/male genital tract.