Targeting serious and sometimes deadly fungal infections, a team of researchers at Worcester Polytechnic Institute (WPI) and the University of Massachusetts Medical School (UMMS) has discovered a chemical compound that prevents fungal cells from adhering to surfaces, which, typically, is the first step of the infection process used by the human pathogen Candida albicans (C. albicans).
Right, C. albicans in its ovoid, harmless state; left, the infectious, filamented state.
After screening 30,000 chemical compounds in a series of tests with live C. albicans, the team found one molecule that prevented the yeast from adhering to human cells or to polystyrene, a common plastic used in many medical devices. Named "filastatin" by the researchers, this molecule now emerges as a candidate for new anti-fungal drug development and as a potential protective material to embed on the surfaces of medical devices to prevent fungal infections.
The 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, reports its findings in the paper "Chemical screening identifies filastatin, a small molecule inhibitor of Candida albicans adhesion, morphogenesis, and pathogenesis," published online in advance of print by the journal Proceedings of the National Academy of Sciences (PNAS).
"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."
Infection by C. albicans causes common chronic illnesses like thrush and vaginitis, which affect millions of people globally each year and are not easily cleared by the handful of anti-fungal drugs now available. While most fungal infections do not cause serious harm, if one spreads to the bloodstream it can be deadly.
Hospitalized patients with catheters or central intravenous lines are at risk as the fungi can grow on those devices and enter the body. Similarly, patients with implanted medical devices like pacemakers or prosthetic hips or knees are also at risk if the implant carries a fungus into the body. Also, people with compromised immune systems are at greater risk for serious fungal infections. Because of 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.
Typically, a blood stream infection of C. albicans or a similar pathogen begins with fungal cells attaching to a surface—a catheter, for example, or epithelial cells lining the mouth—to form what is known as a biofilm. Next, the ovoid shaped yeast cells morph into an invasive filamentous form, extending pointed filaments that penetrate and damage surrounding tissues. In the current study, the team found that filastatin curtailed both steps: it largely prevented C. albicans from adhering to various surfaces, and it significantly reduced filamentation (inspiring the name filastatin).
As a next step, the team tested filastatin's impact on C. albicans cells that had grown unfettered in test wells and had already adhered to the polystyrene walls. When the compound was added to the culture mix, it knocked off many of the fungal cells already stuck to the polystyrene. The inhibitory effects of filastatin were further tested on human lung cells, mouse vaginal cells, and live worms (C. elgans) exposed to the fungus to see if it would reduce adhesion and infection. In all cases, the novel small molecule had significant protective effects without showing toxicity to the host tissues.
Research is now focused on teasing out the precise molecular mechanisms 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."
Additional 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, agreed. "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."
Eileen Mell | EurekAlert!
Satellites, airport visibility readings shed light on troops' exposure to air pollution
09.12.2016 | Veterans Affairs Research Communications
Oxygen can wake up dormant bacteria for antibiotic attacks
08.12.2016 | Penn State
Physicists of the University of Würzburg have made an astonishing discovery in a specific type of topological insulators. The effect is due to the structure of the materials used. The researchers have now published their work in the journal Science.
Topological insulators are currently the hot topic in physics according to the newspaper Neue Zürcher Zeitung. Only a few weeks ago, their importance was...
In recent years, lasers with ultrashort pulses (USP) down to the femtosecond range have become established on an industrial scale. They could advance some applications with the much-lauded “cold ablation” – if that meant they would then achieve more throughput. A new generation of process engineering that will address this issue in particular will be discussed at the “4th UKP Workshop – Ultrafast Laser Technology” in April 2017.
Even back in the 1990s, scientists were comparing materials processing with nanosecond, picosecond and femtosesecond pulses. The result was surprising:...
Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...
A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.
Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...
In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.
“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...
16.11.2016 | Event News
01.11.2016 | Event News
14.10.2016 | Event News
09.12.2016 | Life Sciences
09.12.2016 | Ecology, The Environment and Conservation
09.12.2016 | Health and Medicine