Fungal infections can be mild or life-threatening. They can pose a serious risk to people with a compromised immune system. Some infections are becoming resistant to current treatments. New compounds are being developed that are active against a range of fungi, including resistant strains. The aim is to reduce deaths from overwhelming fungal infection.
Fungi include both yeasts and moulds. Thousands exist and a few infect humans. Of these, some invade the skin, causing mild infections, such as ringworm and athlete’s foot. Yeasts, especially Candida species, infect the mucous membranes of the orifices of the human body, e.g. mouth or vagina, and cause thrush.
Aspergillus niger, Candida albicans, Pneumocystis carinii and Cryptococcus can also invade the body in patients with a compromised or suppressed immune system such as patients with cancers or AIDS or after organ transplantation and cause life-threatening systemic infections, often referred to as opportunistic infections.
Anyone can pick up minor fungal infections of the skin or nails. But infections requiring hospital treatment, especially invasive candidiasis and aspergillosis, have doubled in the past 15 years to around four per 1000 patients - they are the hidden killers, reflecting the increased use of immunosuppressive therapy in cancer and transplantation, which allow infections to take hold more easily.
Patients undergoing surgery form the largest at risk group for such invasive infections and a recent analysis has shown that preventive use of an antifungal medication can reduce invasive fungal infections by a half and overall deaths by a quarter.
Autopsies performed in a large European university hospital to determine trends in invasive fungal infections yielded a rise in prevalence from around 2.5 per cent in the 1980s to five per cent in the most recent years. Besides the emergence of mixed and unclassified infections, this was mainly due to a significant increase in Aspergillus infections, whereas the prevalence of Candida infections was stable. The highest infection rates were found in aplastic syndromes, followed by acute myeloid leukaemia and AIDS. In more than three quarters of cases, invasive fungal infection was related to the immediate cause of death.
Medicines play a major role in the treatment of local and systemic fungal infections.
One class of powerful antifungal molecules, the ‘azoles’, hold most of the top places for antifungal medicines. They work by blocking the formation of ergosterol, a key component of fungal cell membranes.
One, a halogenated azole-derivative, is able to cure candidiasis with a single oral dose, is active against cryptococcal meningitis in AIDS patients, and also has a role in preventing infection in transplant recipients. However, as with bacteria, resistant strains are becoming an increasing problem. Two newer azole antifungals, both of which are indicated for use in invasive fungal infections, may help in this respect.
A second key medicine for systemic infections is a polyene antibiotic. Though no longer new, it still has an important role. Lipid based versions and the liposome-encapsulated formulation show less kidney toxicity and can be given at a higher dose than the conventional preparation.
Another orally administered antifungal acts by inhibiting the enzyme squalene epoxidase, which is also involved in the production of ergosterol. It is mainly used for the treatment of skin and nail infections. Development is also underway to test squalene-epoxidase inhibitors as a treatment for systemic fungal infections.
A completely new class of antifungal agents is represented by a compound that belongs to the echinocandin family of antifungals, which block the production of a major component of the cell wall called 1,3-beta glucan and are effective in killing fungi, rather than just stopping them growing.
The echinocandin molecules act by inhibiting the enzyme 1,3-beta-glucan synthase, meaning that they lack cross-resistance with other antifungal agents. The first molecule in class has been developed for the intravenous treatment of invasive aspergillosis and invasive candidiasis and for the treatment of suspected fungal infections in patients with fever who have low levels of white blood cells.
Finding fungal ‘magic bullets’ depends on pinpointing an essential biochemical step unique to the fungus which can then be blocked. At the same time, the step must not be critical for the survival of human cells, or they may also be killed. This combination of potency and specificity is hard to find, as fungal metabolism is very similar to that of humans.
Further compounds of the new class of echinocandin antifungals are in development. They are effective against yeasts such as Candida and some (but not all) moulds, such as Aspergillus. They are being developed for oesophageal candidiasis, invasive candidiasis and aspergillosis. Investigators are also studying whether they are effective in improving or clearing symptoms of oesophageal candidiasis in people with AIDS.
Three new azole antifungals are also in development. They consist of a broad-spectrum molecule with fungicidal activity against Aspergillus and Fusarium species, while also acting against certain types of resistant Candida. The second compound is effective against a broad variety of pathogens, including Candida and Aspergillus.
It is also developed as a cream to treat the scalp infection tinea capitis in children. The third new broad-spectrum azole is also a topically applied agent of a new type, with both antifungal and antibacterial activity, for fungal skin infections.
With several compounds in development, the range of treatment options, especially for systemic fungal infections, looks set to be greater than for many years. Nevertheless, the constant emergence of resistant strains is a factor that will make necessary continuing efforts to pinpoint the small but distinctive weak points of fungal cells that can be exploited to eliminate them.
As with bacteria, the “micro-cosmos” of yeasts and moulds undergoes steady changes and resistant strains are a major challenge. Therefore, research into hitherto unknown structures must and will continue. Recently, several derivatives of sordarin have been identified, a class of molecules which inhibit a target involved in fungal protein production called translation elongation factor 2.
Recently, scientists have shown that a benzoxaborole antifungal medicine can inhibit yeast by interfering specifically with the reaction that is vital in maintaining the fidelity of the genetic code of the organism. The boron atom in the oxaborole ring is critical for this effect, suggesting that incorporating boron into small molecule antifungals may lead to the production of additional classes of therapeutic agents.
In December 2005, an international consortium of researchers cracked the genetic map for the fungus Aspergillus fumigatus, which is the leading infectious cause of death in vulnerable leukaemia and bone marrow transplant patients. Identifying this genome sequence will transform scientific understanding of why this fungus is so lethal. The importance of the project in helping develop new medicines and diagnostic tests, and understand and prevent diseases like pneumonia and sinusitis cannot be overestimated.