Behind the Paper : A Novel Small Molecule Inhibitor Of Candida Albicans Biofilm Formation, Filamentation And Virulence With Low Potential For The Development Of Resistance
The npj Biofilms and Microbiomes team asked me to talk about the research behind our paper, published earlier this year in the journal. Here’s what we discussed…
npj Biofilms and Microbiomes: What was the main aim of your research and why did you decide to investigate this?
Our main objective for this paper was to identify novel compounds that could inhibit formation of biofilm by Candida albicans. This is an opportunistic pathogenic fungus capable of causing infections, candidiasis, which unfortunately carry high mortality rates.
The incidence of these infections has increased dramatically in the last few decades, mostly because of the expanding population of immunosuppressed and medically-compromised patients, to the point that invasive candidiasis is now the third/fourth most frequent infection in hospitals. The main problem is that fungi are eukaryotic, so (unlike bacteria) there is a very limited arsenal of antifungal drugs to begin with, and to make matters worse, formation of biofilms leads to high level of resistance against most antifungals used in the clinics.
Our thinking is that overall any addition to the antifungal drug armamentarium should be welcome. In particular for this study, we decided to search for small molecule compounds with inhibitory activity against C. albicans biofilm formation. Biofilm formation represents a major virulence factor in C. albicans, so this falls within the realm of ‘anti-virulence’ approaches for antibiotic drug development, which are gaining some traction lately.
How did you go about designing your study?
Previously we have developed a relatively simple and economical model of C. albicans biofilm formation using 96-well microtiter plates. One of the advantages of this technique is that is very robust, so we felt that it would be amenable for high content screening. We knew that after identifying initial hits, their characterization should be relatively quick since most of the required in vitro and in vivo tests were already well established in our laboratory.
“As an academic laboratory, we did not have the luxury of expensive robotic machines for high throughput screening, so our screening involved a lot of manual labour… However, this was the motivation for us to start a highly productive collaboration with biomedical engineers in our institution for the development of nanobiofilm chips.”
What challenges did you face?
As an academic laboratory, we did not have the luxury of expensive robotic machines for high throughput screening, so our screening involved a lot of manual labour (by a graduate student) to test 20,000 small molecule compounds present in the chemical library. This also meant that it took a long time to complete the primary screening. However, this was the motivation for us to start a highly productive collaboration with biomedical engineers in our institution for the development of nanobiofilm chips, which can speed up the process substantially.
What were the key findings from your research?
In this paper we report on the identification and characterization of one of our main candidates, which displays excellent pharmacological properties and strong biofilm-inhibitory activity both in vitro and in vivo. A notable observation, consistent with the overall theme of an ‘anti-virulence’ strategy, is that we could not induce resistance against this compound even after many serial passages.
“The ultimate goal is to help patients suffering from these devastating infections, and there is a very dire and urgent need for better antifungal drugs.”
What next? What further research is needed in this area?
We realize that drug development is a ‘monster’ and at some point needs to be done outside academia, but our main goal is to move this compound through the development pipeline as far as possible. We need to keep in perspective that the ultimate goal is to help patients suffering from these devastating infections, and there is a very dire and urgent need for better antifungal drugs, so we will try to do our best in this regard.
Image: Candida albicans biofilm