Abstract
Invasive candidiasis caused by Candida albicans and non-albicans Candida (NAC) present a serious disease threat. Although the echinocandins are recommended as the first line of antifungal drug class, resistance to these agents is beginning to emerge, demonstrating the need for new antifungal agents. Host defense peptides (HDP) exhibit potent antifungal activity, but as drugs they are difficult to manufacture efficiently, and they are often inactivated by serum proteins. HDP mimetics are low molecular weight non-peptide compounds that can alleviate these problems and were shown to be membrane-active against C. albicans and NAC. Here, we expand upon our previous works to describe the in vitro and in vivo activity of 11 new HDP mimetics that are active against C. albicans and NAC that are both sensitive and resistant to standard antifungal drugs. These compounds exhibit minimum inhibitory/fungicidal concentration (MIC/MFC) in the µg/mL range in the presence of serum and are inhibited by divalent cations. Rapid propidium iodide influx into the yeast cells following in vitro exposure suggested that these HDP mimetics were also membrane active. The lead compounds were able to kill C. albicans in an invasive candidiasis CD-1 mouse model with some mimetic candidates decreasing kidney burden by 3–4 logs after 24 h in a dose-dependent manner. The data encouraged further development of this new anti-fungal drug class for invasive candidiasis.
Highlights
Invasive candidiasis, including candidemia, is a serious fungal infection caused by Candida albicans and non-albicans Candida (NAC) species that can lead to mortality rates as high as 70%, depending on the population sampled [1]
Most compounds were tested for activity against five non-albicans species (NAC): C. tropicalis, C. parapsilosis, C. dublinensis, C. glabrata, and C. krusei
We previously demonstrated that Compound 4 acts on Candida albicans by leading to rapid pore formation [13]
Summary
Invasive candidiasis, including candidemia, is a serious fungal infection caused by Candida albicans and non-albicans Candida (NAC) species that can lead to mortality rates as high as 70%, depending on the population sampled [1]. Many of these NAC spp. are preferentially selected using in diagnosis of invasive candidiasis, and the shift in infection from C. albicans to NAC spp. which prophylactic anti-fungal therapy with fluconazole in the intensive care unit and in are frequently more resistant Many of these NAC spp. are preferentially selected using prophylactic immunocompromised patients [4]. For those infections, patients intolerant of fluconazole are only left with usage of Amphotericin with emergence of the multi-drug resistant C. auris is a concern. We have previously described two new, potent anti-fungal mimetics that are active vitro against both Candida albicans and NAC, even in the presence of 50% human serum, and areinactive against both. New HDP mimetics have potent anti-fungal activity against Candida both in vitro and in vivo In vitro andof inthese vivo. new HDP mimetics have potent anti-fungal activity against Candida both in vitro and in vivo
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