Abstract
Cryptococcus neoformans is an encapsulated yeast responsible for more than 180,000 deaths per year. The standard therapeutic approach against cryptococcosis is a combination of amphotericin B with flucytosine. In countries where cryptococcosis is most prevalent, 5-fluorocytosine is rarely available, and amphotericin B requires intravenous administration. C. neoformans biofilm formation is related to increased drug resistance, which is an important outcome for hospitalized patients. Here, we describe new molecules with anti-cryptococcal activity. A collection of 66 semisynthetic derivatives of ursolic acid and betulinic acid was tested against mature biofilms of C. neoformans at 25 µM. Out of these, eight derivatives including terpenes, benzazoles, flavonoids, and quinolines were able to cause damage and eradicate mature biofilms. Four terpene compounds demonstrated significative growth inhibition of C. neoformans. Our study identified a pentacyclic triterpenoid derived from betulinic acid (LAFIS13) as a potential drug for anti-cryptococcal treatment. This compound appears to be highly active with low toxicity at minimal inhibitory concentration and capable of biofilm eradication.
Highlights
The increased frequency and drug resistance of invasive fungal infections is an expanding public health problem worldwide, which has been neglected over the years [1]
Our study identified a pentacyclic triterpenoid derived from betulinic acid (BA) (LAFIS13) as an efficient future therapeutic molecule, with high activity, low toxicity, and capability to modulate biofilm development
We evaluated a collection of 66 semisynthetic compounds from different sources to select molecules and chemical classes able to cause damage to mature biofilms of C. neoformans B3501
Summary
The increased frequency and drug resistance of invasive fungal infections is an expanding public health problem worldwide, which has been neglected over the years [1]. It is estimated that 1.2 billion people worldwide suffer from such diseases [2]. Cryptococcus neoformans is an encapsulated yeast responsible for more than 180,000 deaths per year [4]. After the inhalation of spores, the yeast reaches the human lungs and efficiently disseminates to the brain, causing meningitis in immunosuppressed hosts [5]. C. neoformans grows as a biofilm in architectural flower-like clusters [6]. The increased resistance of C. neoformans to antimicrobial therapies and host immune mechanisms is associated with its biofilm formation capacity [7]
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