The discovery is important as it signifies the first identification of a specific target for histatin, paving the way for eventually developing a better therapeutic drug for candidiasis.
Candidiasis also is known as thrush, a disease characterised by whitish spots and ulcers on the membranes of the mouth, tongue and throat. It affects primarily people with weakened immune systems caused by antibiotics, chemotherapy or by diseases such as AIDS.
The overall incidence of fungal infections has increased dramatically over the last 20 years according to recent survey data. Infections due to the candida species account for approximately 80 per cent of all major systemic fungal infections.
Researchers were aware that histatin usually can keep Candida albicans in check in persons with enough saliva and a healthy immune system, but they did not know precisely how histatin accomplished this.
The researchers led by Mira Edgerton, discovered that histatin binds to a specific membrane protein called TRK1p, which regulates potassium ion flow through the cell membrane of the pathogenic fungus Candida albicans and allows the cell to regulate its volume.
The binding action of histatin acts like a 'foot in the door', said Edgerton, senior author on the study. "Blocking the channel open allows a lethal unregulated flow of potassium and other essential molecules into, and out of, the cell," she explained.
Candidiasis is a condition that can be treated with antifungal medication in otherwise healthy people, but it is difficult to treat in persons with compromised immunity and can be deadly if it infects vital organs.
Pfizer's Diflucan (fluconazole) and Gyne-Lotrimin, Lotrimin, Mycelex (clotrimazole) are the most commonly prescribed treatments for oral candidiasis. Other approved therapies include Nizoral (ketoconazole) and nystatin.
Through a series of studies at the University at Buffalo in the US, the researchers identified the target-binding protein on Candida albicans by creating mutant strains of the fungus without the target and exposing the mutants to histatin. Results showed that histatin was significantly less active when the suspect target was missing.
Further research indicated that histatin binding to the target protein killed the fungal cells by preventing it from regulating its ions, the positive and negative charged molecules that move into, and out of, cells. Ions regulate electrostatic pressure between the cells' internal and external environments, which, in turn, regulates their volume and water content. Cells that lose their water content without being able to regulate its re-uptake die rapidly.
"Now that the target for histatin has been identified, we can design a better protein that will be even more effective in binding and holding the channel open, causing even better and more rapid killing of the fungus," said Edgerton.
"In addition, many other pathogenic fungi that cause disease in elderly individuals or AIDS patients also should be able to be killed by histatins or drugs designed to target their potassium channels."
The global market for prescription dermatology products was worth $8 billion (5.9 billion euros) in 2003 and is growing at approximately 10 per cent a year. The global total included a $2.5 billion market for antifungal products and $1.5 billion markets for acne products and for products for dermatitis and psoriasis, the balance being made up of products for miscellaneous minor indications.
The market is very fragmented, with no dominant company, but Johnson & Johnson, Novartis, Roche and Schering-Plough are all significant participants.