Jan S. Tkacz

The fungal cell wall as a drug target

Fungal infections are increasingly common and, in certain vulnerable patients, can be serious and even life threatening. The fungal cell wall, a structure with no mammalian counterpart, presents an attractive therapeutic target. Inhibitors of the synthesis of one cell-wall component, beta-(1,3)-glucan, are currently under development as antifungal and antipneumocystis agents.

Antifungals: what's in the pipeline.

The therapeutic landscape for mycotic infections is shifting. New generation azoles that are active against clinically relevant, drug-resistant fungal pathogens have improved bioavailability, half-lives and safety profiles. Acylated cyclic peptide inhibitors of beta(1,3)glucan synthesis with origins as fungal metabolites provide an alternative and highly-selective mode of action, targeting cell-wall biogenesis in important pathogens such as Candida and Aspergillus species. The development, in each structural class, of compounds that have advanced to late-stage clinical trials is summarized in this review.

Pramanicin, a novel antimicrobial agent from a fungal fermentation

Abstract The antimicrobial agent pramanicin ( 1 ), and a related fatty acid ( 6 ), were isolated from a corn-based solid or a lactose-containing liquid fermentation of a sterile fungus found growing in grass. The structures of these compounds were determined by a variety of spectral means including UV, IR, and NMR spectroscopy, as well as mass spectrometry. A number of chemical derivatives are also presented here. Pramanicin represents a new class of antimicrobial agents containing a highly functionalized head group and functionalized fatty side chain

Tremorgenic mycotoxins, paspalitrem A and C, from a tropical Phomopsis

An endophytic Phomopsis sp. from living bark of Cavendishia pubescens in Colombia produced paspalitrem A and paspalitrem C in batch fermentations. These compounds previously were known only from sclerotia of Claviceps paspali as tremorgenic mycotoxins causing neurological disorders of livestock. A potential ecological role of these metabolites in regard to endophytism of the woody host is considered.

Ophiobolin M and analogues, noncompetitive inhibitors of ivermectin binding with nematocidal activity

A series of ophiobolins were isolated from a fungal extract based on their nematocidal activity. These compounds are non-competitive inhibitors of ivermectin binding to membranes prepared from the free-living nematode, Caenorhabditis elegans, with an inhibition constant of 15 microM. The ophiobolins which were most potent in the biological assays, ophiobolin C and ophiobolin M, were also the most potent compounds when evaluated in a C. elegans motility assay. These data suggest that the nematocidal activity of the ophiobolins is mediated via an interaction with the ivermectin binding site. The isolation, structure and biological activity of ophiobolins have been described.

Improvement in the titer of echinocandin-type antibiotics: a magnesium-limited medium supporting the biphasic production of pneumocandins A0 and B0.

SummaryWe have developed a liquid fermentation medium for the submerged culture of the fungus,Zalerion arboricola, which supports the rapid production of an echinocandin-type antibiotic, pneumocandin A0 (formerly L-671, 329), in yields increased at least 4-fold over those reported previously. The improvements were achieved through medium simplification, substitution of high levels of mannitol for glycerol as the major source of carbon, and restriction of available magnesium. Antibiotic formation in batch cultures with this mannitol-based medium is not confined to the idiophase; rather production appears to be biphasic, with synthesis beginning during growth (i.e., at day 3) and increasing in rate at day 11, well after rapid growth has ended. Accumulation of antibiotic continues beyond 14 days, and by 21 days titers greater than 500 μg/ml are attained. For the synthesis of a related compound, pneumocandin B0, by a mutant strain ofZ. arboricola, the medium gives similar production kinetics and a titer of 800 μg/ml. Although supplementation of the medium with magnesium ions stimulates growth, it decreases titer by preferentially affecting the second phase of antibiotic synthesis. This decline in synthesis in the magnesium-supplemented medium is explained by the depletion of mannitol before the second phase of synthesis can begin. In contrast, mannitol in the magnesium-limited medium is used more slowly with approximately half still available at day 11 to support continued antibiotic formation.