Fungal Infections and Antimycotic Drugs

Fungal Infections

While bacterial and viral infections have received extensive media attention, the threat of fungal infections (mycosis) has been mostly ignored. However, for people with a less than effective immune system, e.g. AIDS patients, burn victims, and individuals undergoing chemotherapy, fungal infections are a serious concern, and can in fact be life-threatening. As a consequence of the increase in immuno-compromised individuals, and the development of resistance by fungi, a steady increase in severe systemic mycoses has been observed. To illustrate this, the number of deaths directly caused by fungal infections more than quadrupled, between 1977 and 1997 in the United States, despite the improvements in healthcare.

Development of Antimycotic Drugs

Surprisingly, the variety of drugs available for the treatment of fungal infections (antimycotic drugs) is extremely limited. The standard therapy for the treatment of mycoses is an azole antifungal agent, such as Fluconazole. However, if resistance develops for one of these drugs than the only possible treatment left is Amphotericin B. Unfortunately, Amphotericin B requires intravenous administration and thus hospitalization. Because of the limited treatment options and the presence of resistance mechanisms against all currently available treatment options, it is imperative that novel antimycotic drugs are developed.

Several options are available to develop novel antimycotic drugs. One of the most promising strategies is developing inhibitors to enzymes that are essential for the survival of fungi. However, a complicating factor is that, since fungi and humans are both eukaryotes, many of these "essential" enzymes are present in both species. This implies that inhibitors to these enzymes would not only cure the fungal infection, but also kill the patient. Fortunately, there are essential fungal enzymes which have no homologues in humans, e.g. enzymes involved in the biosynthesis of essential amino acids.

Aspartate Pathway

The synthesis of the essential amino acids threonine, isoleucine and methionine occurs via the aspartate pathway in fungi. Any of the enzymes which make up this pathway is a potential target for structure-based drug design of antimycotic drugs. We are pursuing the x-ray crystallographic structure determination of several enzymes of the aspartate pathway. These structures can subsequently be used in the development of specific inhibitors that have antimycotic properties.

Progress Made (see Publications)

The structure of the aspartate pathway enzyme homoserine dehydrogenase has been elucidated by X-ray crystallographic techniques. The structure revealed a unique fold and a unique reaction mechanism that was not previously observed in other related enzymes. These observations are extremely encouraging for the development of specific inhibitors to this enzyme.
[See also our Gallery for figures of homoserine dehydrogenase]

Current Research and Future Directions

The Berghuis Lab is pursing the structure determination of several other aspartate pathway enzymes. Furthermore, given the structure of homoserine dehydrogenase, the door is now open to pursue the development of specific inhibitors to this enzyme. Currently, several inhibitors for homoserine dehydrogenase have been developed (lead compounds), and examination by X-ray crystallographic techniques is in progress. These studies will aid in making improvements to these lead compounds, and in time will lead to an effective antimycotic treatment.

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