New compound discovered for treating fungal infections

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New compound discovered that prevents fungal infections from developing
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A chemical compound that prevents fungal cells from adhering to surfaces has been discovered by researchers targeting serious and sometimes deadly fungal infections.

Preventing fungal cells from sticking to surfaces is the usual first step of the infection process used by the human pathogen Candida albicans (C. albicans).

The discovery was made after researchers at Worcester Polytechnic Institute (WPI) and the University of Massachusetts Medical School (UMMS) screened 30,000 chemical compounds in a series of tests with live C. albicans and found one molecule that prevented the yeast from adhering to human cells, as well as a common plastic used in many medical devices.

Named "filastatin" by the researchers, this single molecule opens the door to a new anti-fungal drug development, not to mention its use as a potential protective substance that could be put on medical device surfaces to prevent fungal infections.

These findings were reported by the research team – led by co-principal investigators Paul Kaufman, PhD, professor of molecular medicine at UMMS, and Reeta Rao, PhD, associate professor of biology and biotechnology at WPI – in an article titled "Chemical screening identifies filastatin, a small molecule inhibitor of Candida albicans adhesion, morphogenesis, and pathogenesis”, which was published online in the journal Proceedings of the National Academy of Sciences (PNAS) in advance of the print version.

"In humans, the most widespread fungal pathogen is Candida albicans, which is also one of the most frequent causes of hospital-acquired infections," the authors write. "We conclude that filastatin is not toxic to the human cell line under our assay conditions, but is unique in that it can impair fungal adhesion both to inert surfaces and to cultured human epithelial cells."

Common chronic illnesses, such as thrush and vaginitis, can be caused by C. albicans infection, which affect millions of people worldwide each year. Such infections are difficult to clear, and only a few anti-fungal medications are currently available.

Although most fungal infections do not cause serious harm, if just one gets into the bloodstream, it can result in death.

Those especially at risk are hospitalized patients with catheters or central intravenous lines, where the fungi can grow and enter the body. Patients with implanted medical devices, including pacemakers or prosthetic hips or knees, are also at risk if the device has a fungus that gets into the body. Similarly, those with compromised immune systems have a higher risk of developing serious fungal infections. Due to the lack of effective drugs against C. albicans and other pathogenic fungi, the mortality rate for systemic fungal infections is between 30 and 50 percent.

In a two-step process, a blood stream infection of C. albicans (or a similar pathogen) typically starts developing with fungal cells attaching to a surface, such as a catheter for example, which then forms a film that morphs into invasive pointed filaments that penetrate and damage surrounding tissues.

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In this study, the researchers found that filastatin actually curtailed these two steps by: 1) largely preventing C. albicans from adhering to various surfaces; and 2) by significantly reducing the formation of invasive filaments.

In a third step, the research team next tested filastatin's impact on C. albicans cells that had already proliferated in test wells and started adhering to walls made of the common plastic material, polystyrene. However, when they added the compound to the culture mix, it removed many of the fungal cells already adhered to the plastic.

In addition, the inhibitory effects of filastatin were further tested on human lung cells, mouse vaginal cells, and live worms (C. elgans) that had been exposed to the fungus to see if it would reduce adhesion and infection. In all cases, the filistatin molecule demonstrated significant protective effects without showing toxicity to the host tissues.

Current research is now focused on luring out the precise molecular mechanisms that filastatin uses to prevent adhesion and filamentation.

"We need to find the target of this molecule," Rao said. "We have some good leads, and the fact that we aren't seeing toxicity with host cells is very encouraging, but there is more work to be done."

Meanwhile, more studies on filastatin are underway at both WPI and UMMS.

"The molecule affects multiple clinically relevant species, so we're pursuing the idea that it provides a powerful probe into what makes these organisms efficient pathogens," Dr. Kaufman said. "In this era of budget gridlock in Washington, our ability to get funding from the Center for Clinical and Translational Research at UMMS to support this work was essential for allowing us to pursue our ideas for novel ways to approach this important class of hospital-acquired infections."

The project was also funded by a grant from a WPI/UMMS pilot program established to promote collaborations between researchers at the universities to advance early stage translational research.

"Joint research programs, such as the pilot program between our institutions, are central to WPI's work in the life sciences," said Michael Manning, PhD, associate provost for research ad interim, at WPI. "As this collaboration between Professors Rao and Kaufman demonstrates so well, both institutions can leverage their complementary expertise for the ultimate advancement of scientific discovery and public health."

Terence R. Flotte, MD, UMMS executive deputy chancellor, provost, and dean of the School of Medicine, agrees.

"The faculty of UMass Medical School and WPI possess scientific knowledge and expertise in disciplines that complement each other," he said. "The creation of this type of multidisciplinary team collaboration between the two universities allows us to work synergistically to solve problems important for improving human health."

SOURCE: A. Fazly, C. Jain, A. C. Dehner, L. Issi, E. A. Lilly, A. Ali, H. Cao, P. L. Fidel, R. P. Rao, P. D. Kaufman. Chemical screening identifies filastatin, a small molecule inhibitor of Candida albicans adhesion, morphogenesis, and pathogenesis. Proceedings of the National Academy of Sciences, 2013; 110 (33): 13594 DOI: 10.1073/pnas.1305982110

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