It seems logical, at least on paper, to propose that such information, coupled with the known mechanisms whereby resistance (which may be a problem) to flucytosine arises, might lead to the devlopment and design of more potent antifungal inhibitors.

Sub-inhibitory concentrations of amphotericin enhance the fungicidal properties of flucytosine against C. albicans, with a markedly increased incorporation of 5-fluorouracil into RNA. It is interesting to speculate that polyenic-induced membrane damage to the fungal cell membrane is responsible for an increased intracellular uptake of flucytosine with a consequent increased deamination to 5-fluorouracil. The effect is most pronounced in flucytosine-resistant C. albicans. Certainly the mixture has proved to be of value in experimental chemotherapy in animals. One problem always associated with flucytosine, however, is the risk of bone-marrow depression.

11.7.5 Other membrane-active compounds

The synthetic thiocarbamates, of which tolnaftate (11.133) is an example, have been found to inhibit squalene epoxidase. The enzyme converts squalene, the first lipophilic intermediate in the sterol pathway, to the 2,3-oxide. Thiocarbamates have been used to treat dermatophyte infections for many years. Interestingly, tolnaftate (11.133) inhibits epoxidase from C. albicans, but is inactive against whole cells, presumably due to inability to penetrate the cell wall.

The synthetic allylamines also inhibit squalene epoxidase. They are highly selective for the fungal sterol biosynthetic pathway and often have fungicidal effects against a broad spectrum of fungi. Terbinafine (11.134) is the best-selling non-azole drug and is normally used to treat skin, nail and hair infections. However, there are signs that terbinafine (11.134) may have a broader spectrum of activity with potential for treating systemic infections too.

The morpholines are characterized by a 2,6-dimethylmorpholine ring with a bulky N-substituent. Amorolfine (11.135) has been developed as a topical antifungal. Amorolfine

inhibits A8-7 isomerase and A14 reductase, causing hyperfluidity of the membrane with an irregular deposition of chitin. Treated cells accumulate sterols. Amorolfine (11.135) has a broad spectrum of activity, but is not absorbed orally, and is undergoing clinical trials as a topical agent.

11.7.6 Cell wall-active compounds

The polyoxins and nikkomycins (neopolyoxins) are peptido-nucleosides, structural analogues of a cell wall precursor, uridine diphosphate N-acetylglucosamine. They are highly specific competitive inhibitors of chitin synthase, causing marked morphological changes leading to cell lysis.

The polyoxins (e.g. polyoxin D (11.136)) were isolated from Streptomyces cacoi and the closely related nikkomycins (e.g. nikkomycin Z (11.137)) from S. tendae. Nikkomycins tend to be more active against whole cells, presumably due to better transport into the cell. Despite the promise of these compounds, little in vivo testing seems to have been performed, though some reports have shown significant activity against Histoplasma capsulatum and some yeasts and dermatophytes. The recent discovery that many fungi produce multiple chitin synthases of varying susceptibilies to these compounds highlights the problems of designing adequate agents, particularly for medically important fungi.

Many fungal walls contain glucose polymers known as glucans joined through a-and P- (1,3) or (1,6) linkages. The echinocandins (e.g. echinocandin B (11.138)) are cyclic hexapeptides in which all of the amino acid residues contain hydroxyl groups.

All possess a lipophilic side-chain (derived from linoleic acid). Cilofungin (11.139), a semi-synthetic derivative of echinocandin B (11.138), was developed for clinical use but was withdrawn due to toxic effects. These compounds have two major drawbacks as potential clinical agents: (a) a narrow spectrum of activity, and (b) poor solubility in pharmacologically acceptable solvents. It is also apparent that these compounds inhibit the assembly of P-1,3 and P-1,6 linked glucans and not a-linked glucans. Thus, they are highly active

against Candida, which contains large quantities of P-linked glucans, but are inactive against Cryptococcus, which contains mainly a-1,3-glucan.

11.7.7 Novel antifungal agents

The increasing population of immunocompromised patients (those with AIDS, those undergoing organ transplants, or those receiving anticancer chemotherapy) is at risk from disseminated fungal infections. Amphotericin B (11.121) is the only fungicidal agent widely used for treatment in this group of patients, but unfortunately it is toxic for many. Novel fungicidal agents with little or no toxicity are therefore required. Attempts are being made to rationally design drugs targeted at specific fungal enzymes. Such enzymes include the DNA topoisomerases, which are essential in maintaining the topological structure of DNA and are involved in such processes as DNA supercoiling and DNA replication. Topoisomerases are found in both humans and fungi and the crucial question is whether the biochemical differences are sufficient to allow selective targeting with minimal toxicity. Two experimental agents are under investigation. The aminocatechol A-3253 (11.140) is approximately ten-fold more active against Candida topoisomerase I than human topisomerase I. The compound also inhibits P-1,3-glucan synthesis (see Section 11.7.6). A second experimental agent, the isothiazoloquinolone A-75272 (11.141), targets topoisomerase II and possesses equivalent activity against the fungal and mammalian enzymes. Nevertheless, such compounds may serve as useful starting points in the rational design of antifungal agents based on the different biochemical properties of fungal enzymes.

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