Azole-Based Compounds That Are Active against <i>Candida</i> Biofilm: In Vitro<i>,</i> In Vivo and In Silico Studies

• Main Authors: Simone Carradori (Author), Alessandra Ammazzalorso (Author), Barbara De Filippis (Author), Ahmet Fatih Şahin (Author), Atilla Akdemir (Author), Anastasia Orekhova (Author), Graziana Bonincontro (Author), Giovanna Simonetti (Author)
• Format: Book
• Published: MDPI AG, 2022-10-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/antibiotics11101375; 2079-6382
• Keywords: azoles; antifungal agents; antibiofilm; <i>Candida</i>; dermatophytes; <i>Aspergillus</i>; Therapeutics. Pharmacology; RM1-950
• Source: Antibiotics, Vol 11, Iss 10, p 1375 (2022)

Fungal pathogens, including <i>Candida</i> spp., <i>Aspergillus</i> spp. and dermatophytes, cause more than a billion human infections every year. A large library of imidazole- and triazole-based compounds were in vitro screened for their antifungal activity against <i>C. albicans</i>, <i>C. glabrata</i>, <i>C. krusei</i>, <i>A. fumigatus</i> and dermatophytes, such as <i>Microsporum gypseum, Trichophyton rubrum</i> and <i>Trichophyton mentagrophytes</i>. The imidazole carbamate <b>12</b> emerged as the most active compound, showing a valuable antifungal activity against <i>C. glabrata</i> (MIC 1-16 μg/mL) and <i>C. krusei</i> (MIC 4-24 μg/mL). No activity against <i>A. fumigatus</i> or the dermatophytes was observed among all the tested compounds. The compound <b>12</b> inhibited the formation of <i>C.</i> <i>albicans</i>, <i>C.</i> <i>glabrata</i> and <i>C.</i> <i>krusei</i> biofilms and reduced the mature <i>Candida</i> biofilm. In the <i>Galleria mellonella</i> larvae, <b>12</b> showed a significant reduction in the <i>Candida</i> infection, together with a lack of toxicity at the concentration used to activate its antifungal activity. Moreover, the in silico prediction of the putative targets revealed that the concurrent presence of the imidazole core, the carbamate and the <i>p</i>-chlorophenyl is important for providing a strong affinity for lanosterol 14α-demethylase (CgCYP51a1) and the fungal carbonic anhydrase (CgNce103), the <i>S</i>-enantiomer being more productive in these interactions.