Antifungal Proteins

Fungi are amazing organisms, being able to use almost any surface (e.g., bathroom tile, skin, or leaves) for growth. Unfortunately, they also are proficient at colonizing and using plants, humans, and animals as substrates. During the last two decades, the incidence of human fungal infections, especially involving immunocompromised patients, has dramatically increased (27, 41, 57). This is in part due to the tremendous advances in medicine that permit the saving of patients with neoplastic and immunocompromising diseases who would otherwise not have survived. It is ironic that many of these patients succumb to fungal infections for which there are few or no drugs available for treatment. Encouragingly, naturally occurring antifungal proteins and peptides, as well as synthetic derivatives, have the potential to be very interesting clinical leads. Fungi are an extremely diverse group of organisms, with about 250,000 species widely distributed in essentially every ecosystem. Muller and Loeffler (124) estimate that the weight of fungi on Earth exceeds that of humans; Armillaria bulbosa, a tree root pathogen, is reported to be among the largest and oldest organisms on the planet (162). Humans and other animals are exposed to fungi from the moment of birth. Fortunately, only 200 or so species are pathogenic to mammals, although many nonpathogenic fungi cause allergy symptoms (3). The majority of fungal exposures and infections are selflimiting in intact animal hosts (76). However, in patients with compromised immune systems, infections even by fungal organisms with low virulence can be life threatening; for example, systemic fungal infections of leukemia patients account for 50% of fatalities (101, 141). Nosocomial bloodstream infections have a similar fatality rate (107). Plants are also exposed to a large number of pathogenic fungi; although they do not have an immune system, plants have evolved a variety of potent defense mechanisms, including the synthesis of low-molecular-weight compounds, proteins, and peptides that have antifungal activity (16, 18, 47, 80, 104, 127, 151, 159, 177). Similarly, bacteria, insects, mollusks, fungi, and mammals synthesize a number of proteins and peptides that are antifungal (13, 19, 20, 30, 49, 51–54, 58, 68, 69, 79, 83, 109–111, 122, 126, 128, 153, 188, 189, 192). These proteins appear to be involved in either constitutive or induced resistance to fungal attack. It is a testament to the efficacy of these defenses that plants and animals, including humans, do so well against pathogenic fungi. There are hundreds of antifungal peptides and proteins known, with more being discovered almost daily. This brief review will focus on proteins with molecular masses of greater than ;5 kDa, about 50 amino acids in length; this choice is somewhat arbitrary, for there is not consensus concerning where a peptide ends and a protein begins. Even eliminating the small proteins (peptides), the list of antifungal proteins is large and daunting. The reader is directed to a review concerning antifungal peptides and proteins of less than 5 kDa (30). Given the diverse and varied types of proteins, this review will be an overview of the primary classes of antifungal proteins. Thirteen classes of antifungal proteins will be described: PR-1 proteins, (1,3)b-glucanases, chitinases, chitin-binding proteins, thaumatin-like (TL) proteins, defensins, cyclophilin-like protein, glycine/histidine-rich proteins, ribosome-inactivating proteins (RIPs), lipid-transfer proteins (LTPs), killer proteins (killer toxins), protease inhibitors, and other proteins. These proteins have been named primarily on the basis of either their mechanism of action, (e.g., glucanases), their structure (e.g., cysteine rich), or their similarity to a known “type” protein. To confuse the nomenclature further is the fact that several proteins can be and have been classified into more than one group. It is unfortunate that a standard nomenclature based on structure or some other unifying property(ies) of these proteins has not been proposed or adopted.