Two-faced drugs fight hidden killers

by Jordan Reese
Two-faced drugs fight hidden killers
An outbreak of fungal meningitis recently killed 32 people in the United States and sickened more than 400.

(Medical Xpress)—An outbreak of fungal meningitis recently resulted in one of the worst public health disasters in recent U.S. history. Thirty-two people died and more than 400 became ill after the New England Compounding Center distributed contaminated vials of injectable steroids.

are clamoring for stricter regulation of so-called compounding pharmacies, which until now have flown under the radar of the . Of major health concern in cases like this is the nature of the infections themselves. Hiding behind the blood-brain barrier, or BBB, a concept every first-year biology or psychology student is familiar with, these infections escape direct contact with most medications and require patients to endure long and sometimes unsuccessful treatment with antibiotics.

Steven Regen, University Distinguished Professor of chemistry, is working at the forefront of efforts to treat fungal meningitis that hides behind that barrier. Regen conducts research in the field of membranes and drug delivery with Vaclav Janout, senior research scientist, and Celine Bienvenu, postdoctoral research associate, both in the department of chemistry. With funding from the National Institutes of Health, they are seeking to develop a new class of drugs that can pierce the BBB and provide effective treatment for fungal meningitis and a host of other diseases in the brain.

A new paradigm for drug transport

"In a broader context," said Regen, "if we have any luck with our approach it could establish a new paradigm for the transport of many other drugs into the ."

The BBB consists of tightly packed that separate circulating blood from cerebrospinal fluid in the central nervous system. One of the greatest challenges facing is the search for drugs that can be transported across that barrier. Many classes of drugs with the potential for treating (fungal and bacterial infections, malignant tumors, neurodegenerative diseases, etc.) have minimal effectiveness because of their limited ability to cross the BBB.

Regen’s lab has developed a class of amphiphilic molecules that assume different morphological states in response to changes in microenvironment. Like an umbrella, the compounds cover an attached agent and shield it from an incompatible environment.

One example is amphotericin B (AmB), an antibiotic currently used to treat . Because AmB does not readily cross the BBB, and because it is highly toxic, its overall effectiveness is limited.

Regen's team has been asked by NIH to create a new class of AmB agents based on what Regen calls molecular umbrellas. These structures are a novel class of amphiphiles, or chemical compounds whose exteriors are both hydrophobic and hydrophilic and thus ideal for crossing hydrophobic membranes like the BBB.

Dual conformational properties

What makes molecular umbrellas valuable, says Regen, is that they may be able to carry biologically active agents across the BBB in ways that have not previously been possible.

The innovative aspects of this research lie entirely with the unique conformational and transport properties associated with molecular umbrellas. In essence, molecular umbrellas are molecules composed of two or more walls attached to a central scaffold. When immersed in an aqueous environment, a molecular umbrella favors a conformation in which the hydrophobic faces point towards one another, to shield themselves from water.

Conversely, when immersed in a lipophilic environment, the molecular umbrella favors a conformation in which the hydrophilic faces point toward each other and the lipophilic faces point outward. In this case, the hydrophilic faces now become shielded from the external environment. Regen's team calls such behavior "molecular amphomorphism."

Regen's team will test the potential of molecular umbrellas that are chemically attached to AmB to kill fungal cells in cell culture and in animal models. These animal studies will be carried out by Professor John Perfect, a collaborator at Duke University School of Medicine, who is an expert in fungal infections. If, as expected, one or more of the molecular umbrella-AmB combinations prove more effective than simple AmB, there could be good reasons to explore other molecular umbrella-drug combinations for a variety of diseases, possibly even brain tumors.

At a more fundamental level, the research challenges the current dogma that drug transport is limited by molecular size and lipophilicity. In published work, Regen and his team have shown that very large and hydrophilic molecular umbrellas can enter live cells in cell culture experiments. They have also shown that they can cross model membranes that mimic cell membranes.

As they test new compounds, the researchers will learn whether the antibiotic supply in the brain speeds or slows depending on the size and structure of their molecular umbrellas.

add to favorites email to friend print save as pdf

Related Stories

US warns meningitis cases could rise

Oct 12, 2012

US authorities have managed to contact most of the thousands of people exposed to the tainted drug blamed for a meningitis outbreak that has killed 14, but warned the number of infections could rise.

Building the blood-brain barrier

Oct 27, 2008

Construction of the brain's border fence is supervised by Wnt/b-catenin signaling, report Liebner et al. in The Journal of Cell Biology.

Recommended for you

Evidence-based recs issued for systemic care in psoriasis

19 hours ago

(HealthDay)—For appropriately selected patients with psoriasis, combining biologics with other systemic treatments, including phototherapy, oral medications, or other biologic, may result in greater efficacy ...

Bacteria in caramel apples kills at least four in US

20 hours ago

A listeria outbreak believed to originate from commercially packaged caramel apples has killed at least four people in the United States and sickened 28 people since November, officials said Friday.

Steroid-based treatment may answer needs of pediatric EoE patients

20 hours ago

A new formulation of oral budesonide suspension, a steroid-based treatment, is safe and effective in treating pediatric patients with eosinophilic esophagitis (EoE), according to a new study in Clinical Gastroenterology and Hepatology, the official clinical practice journal ...

Discovery of genes that predispose a severe form of COPD

22 hours ago

A study by Ramcés Falfán-Valencia, researcher at the National Institute of Respiratory Diseases (INER), found that the mestizo Mexican population has a number of variations in certain genes that predispose ...

On the environmental trail of food pathogens

Dec 19, 2014

Tracking one of the deadliest food contamination organisms through produce farms and natural environments alike, Cornell microbiologists are showing how to use big datasets to predict where the next outbreak could start.

User comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.