Off-patent drug appears promising as broad-spectrum antifungal

October 31, 2018, American Society for Microbiology

By screening a library of off-patent drugs, scientists have identified a compound with promising broad-spectrum antifungal activity. The compound, alexidine dihydrochloride, warrants further development as a pan-fungal, anti-biofilm drug, according to the research reported in the journal mSphere.

"There are currently only three major classes of antifungal drugs used in the clinic and several pathogenic fungi are resistant to them, so there is an urgent need to identify compounds that have novel molecular targets," said principal study investigator Priya Uppuluri, Ph.D., assistant professor at Los Angeles Biomedical Research Institute at Harbor, University of California at Los Angeles (UCLA) Medical Center, Torrance, California. "Repurposing existing libraries of drugs that are approved for other indications can potentially be used for a new purpose as an antifungal. This can considerably shorten the discovery process."

Fungal pathogens are major drivers of morbidity and mortality, causing over 2 million infections and killing 1.5 million people per year, despite treatment with . Invasive fungal infections due to Candida albicans, Aspergillus fumigatus and Cryptococcus neoformans pose a substantial threat especially to hospitalized immunocompromised patients and others with compromised immune functions.

The severity of infections caused by these pathogens is accentuated due to their ability to develop a multicellular community of cells called "biofilms," on a wide variety of indwelling medical devices including (CVC). Once formed, biofilms serve as a reservoir of cells that have direct access into the vasculature, and cannot be eradicated due to their completely drug-resistant properties. Of concern, said Dr. Uppuluri, is that new strains of multidrug-resistant strains of fungi capable of forming biofilms, such as Candida auris, have emerged. The Centers of Disease Control and Prevention (CDC) has proclaimed C. auris as a serious global threat.

In the new study, researchers from LA Biomed at Harbor-UCLA screened the New Prestwick Chemical Library, a small molecule library of 1,200 FDA-approved, off-patent molecules, to identify compounds capable of simultaneously inhibiting growth of C. albicans, C. auris, and A. fumigatus. They further prioritized inhibitors for their potency against other fungal pathogens including C. auris and on their ability to kill preformed biofilms.

The researchers identified Alexidine dihydrochloride, a drug approved as a topical antimicrobial and anti-plaque agent, as the drug with the greatest antifungal and anti- activity against a diverse range of . This compound significantly potentiated the efficacy of the clinically used azole drug fluconazole against biofilms, displayed low mammalian cell toxicity, and eradicated biofilms growing in mice central venous catheters, in vivo. Their findings highlight the drug's potential for use as a pan-antifungal drug.

"This is one of the first molecules identified that works as a pan-antifungal at very low concentrations, including against biofilms that are completely resistant to all drugs," said Dr. Uppuluri. The researchers are currently working on the medicinal chemistry aspect of synthesizing analogues of Alexidine dihydrochloride, to improve its physiochemical characteristics, and to reduce its toxicity to mammalian cells. Dr. Uppuluri encouraged other researchers to take advantage of the various drug libraries, many available at the Molecular Screening Shared Resources facility at UCLA, to screen molecules for their desired disease indications.

Explore further: First systematic study of deadly, antibiotic-resistant fungus reported

Related Stories

First systematic study of deadly, antibiotic-resistant fungus reported

February 24, 2017
The deadly fungus, Candida auris, which has been found in hospitals, is resistant to entire classes of antimicrobial drugs, limiting treatment options for those infected. First reported in 2009, the fungus has been linked ...

Feijoas promise new anti-fungal treatments says researcher

December 8, 2017
Mona Mokhtari will graduate with a PhD in Biomedical Science at a Victoria graduation ceremony, after conducting research into the antifungal properties of one of New Zealand's favourite fruits.

Fungal disease spreads through UK hospitals – here's what you need to know about _Candida auris_

August 18, 2017
At least 20 NHS Trust hospitals have been hit by a drug-resistant fungus, Candida auris. So far, 200 people have been contaminated or infected with the fungus, which can cause potentially deadly complications.

Novel algorithm predicts drug combinations to treat drug resistant fungal infections

July 14, 2016
Scientists have created an algorithm that can identify drug combinations to treat fungal infections that have become resistant to current drug treatments. This new study, published in PLOS Computational Biology, represents ...

Recommended for you

Infants born to obese mothers risk developing liver disease, obesity

November 16, 2018
Infant gut microbes altered by their mother's obesity can cause inflammation and other major changes within the baby, increasing the risk of obesity and non-alcoholic fatty liver disease later in life, according to researchers ...

New study shows NKT cell subsets play a large role in the advancement of NAFLD

November 16, 2018
Since 2015 it has been known that the gut microbiota could have a direct impact on nonalcoholic fatty liver disease (NAFLD), which affects up to 12% of adults and is a leading cause of chronic liver disease. In the November ...

Antibiotic prescribing influenced by team dynamics within hospitals

November 15, 2018
Antibiotic prescribing by doctors is influenced by team dynamics and cultures within hospitals.

Discovery suggests new route to fight infection, disease

November 14, 2018
New research reveals how a single protein interferes with the immune system when exposed to the bacterium that causes Legionnaires' disease, findings that could have broad implications for development of medicines to fight ...

Zika may hijack mother-fetus immunity route

November 14, 2018
To cross the placenta, Zika virus may hijack the route by which acquired immunity is transferred from mother to fetus, new research suggests.

New research aims to help improve uptake of hepatitis C testing

November 14, 2018
New research published in Scientific Reports shows persisting fears about HIV infection may impact testing uptake for the hepatitis C Virus (HCV).

0 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.