Impact of melanin on microbial virulence and clinical resistance to antimicrobial compounds.

Melanins are negatively charged, hydrophobic pigments of high molecular weight (54, 88, 95, 139) that are composed of polymerized phenolic and/or indolic compounds (Fig. 1) (45, 128). Melanins are produced by organisms in all biological kingdoms, including a wide variety of pathogenic bacteria, fungi, and helminths (reviewed in reference 90). Remarkably little is known about the structures of melanins, despite their abundance in the global biomass. This is due to the inability of current biochemical and biophysical techniques to provide a definitive chemical structure, because these complex polymers are amorphous, insoluble, and not amenable to either solution or crystallographic structural studies. Consequently, our information on the structure of melanin is derived from the analysis of their degradation products and spectroscopic analysis of the melanin polymer (128). Characteristically, melanins are dark in color, insoluble in aqueous or organic fluids, resistant to concentrated acid, and susceptible to bleaching by oxidizing agents (17, 87, 103). Methods for partial chemical degradation of melanin followed by high-pressure liquid chromatographic microanalysis have been developed and are useful for the characterization of specific types of melanin (128, 129). An operational definition for a pigment as a melanin can be provided by electron spin resonance characteristics, since these pigments uniquely are stable organic free radicals (29). Many diverse functions have been attributed to melanins. Melanins can serve as energy transducers and affect cellular integrity (reviewed in reference 48). Melanin is also used for sexual display and camouflage. For instance, the coloration in black and red hair arises from melanin (18). An example in which melanin is used for camouflage is the release of ink, a suspension of melanin particles, by the cuttlefish (Sepia officinalis) in response to danger (34). Melanin plays a major role in the innate immune system of insects, which synthesize the polymer to damage and entomb microbial intruders (85, 104). In insects, invading microbes activate a prophenoloxidase in the hemolymph, resulting in the encasement of the bacterial, protozoal, or fungal pathogen in melanin (78). Melanins in melanocytes in skin provide protection against sunlight and are also believed to contribute to the resistance of melanoma to therapeutic radiation (47). The role of melanin in other circumstances is uncertain, such as melanin in the neurons of the substantia nigra in the human brain (147, 148). In mammals, melanin synthesis is catalyzed by a tyrosinase (114). In contrast, microbes generally synthesize melanin via various phenoloxidases (such as tyrosinases, laccases, or catacholases) and/or the polyketide synthase pathway (reviewed in reference 138). Melanins generated from 3,4-dihydroxyphenyalanine (DOPA) by phenoloxidases are referred to as eumelanins, which are generally black or brown. Yellow or reddish melanins are called pheomelanins and incorporate cysteine with DOPA. Brownish melanins derived from homogentisic acid by tyrosinases are called pyomelanins (144). Melanins formed from acetate via the polyketide synthase pathway are typically black or brown and are referred to as dihydroxynaphthalene melanins. Melanin synthesis has been associated with virulence for a variety of pathogenic microbes. Melanin is believed to contribute to microbial virulence by reducing a pathogen’s susceptibility to killing by host antimicrobial mechanisms and by influencing the host immune response to infection. Consequently, melanin and melanin synthesis pathways are potential targets for antimicrobial drug discovery. Interestingly, the drug-binding properties of both host and microbial melanins could influence the outcome of antimicrobial therapy. This review discusses the impact of melanin production on microbial survival in the environment and during infection, on host immune responses, and on the efficacies of antimicrobial compounds. The capacity for melanin to bind to diverse compounds can affect the testing of antimicrobial drugs and reduce the activity of antimicrobial therapy.