ml-1 were observed in 92% and 63% of the isolates, respectively. C. zeylanoides and C. lipolytica (a rarely observed CNA) showed MIC50–90 values of ≤ 0.03
μg.ml-1 for both inhibitors, whilst C. krusei was resistant to EIL, with MIC50–90 values of 8 μg.ml-1 (Table 3). However, both C. krusei and C. lipolytica were resistant to AZA (MIC50–90 ≥ 16 μg.ml-1) (Table 3). Finally, C. guilliermondii isolates, FLC- and ITC-resistant, were susceptible to AZA, with MIC50–90 values of 0.06 – 0.25 μg.ml-1. Table 3 Antifungal activity of 20-piperidin-2-yl-5α-pregnan-3β,20-diol (AZA) and 24 (R,S),25-epiminolanosterol (EIL), Δ24(25)-sterol methyl transferase inhibitors, against 65 clinical isolates of Candida spp. by the CLSI reference broth microdilution method. Drugs Species (no. of isolates) Concentration (μg.ml-1) range PARP inhibitor of the MICs +MIC50 +MIC90 AZA All species (65) ≤ 0.03 – > 16 0.5 2 Candida albicans (21) 0.06 – > 16 0.5 8 Candida parapsilosis (19) 0.06 – > 16 0.12 0.5 Candida tropicalis (14) 0.06 – > 16 0.62 8 Candida glabrata (2) 0.12 – > 16 1 2 Candida krusei (1) 16 – > 16 16 > 16 Candida lusitaneae (1) 0.06 – 0.5 0.06 0.5 Candida guilliermondii (3) ≤ 0.03 – 0.5 0.06 0.25 Candida zeylanoides (1) ≤ 0.03 ≤ 0.03 ≤ 0.03 Candida rugosa (1) 0.25 – 1 0.25 1 Candida THZ1 concentration dubliniensis (1) 0.5 – 2 0.5 2 Candida lipolytica (1) > 16 > 16 > 16 EIL All species (65) ≤ 0.03 – > 16 2 2
Candida albicans (21) 0.5 – 8 2 2 Candida MGCD0103 clinical trial parapsilosis (19) 0.5 – 8 1 2 Candida tropicalis (14) 1 – 8 1 2 Candida glabrata (2) 0.5 – 4 1 2 Candida krusei (1) 8 8 8 Candida lusitaneae (1) 0.5 – 2 0.5
2 Candida guilliermondii (3) 1 – 4 1 4 Candida zeylanoides (1) 1 – 2 1 2 Candida rugosa (1) 1 – 2 1 2 Candida dubliniensis (1) 2 – 8 2 8 Candida lipolytica (1) ≤ 0.03 ≤ 0.03 ≤ 0.03 +MIC results are medians. Correlations between MIC values Positive correlations of the MIC50 values were observed between AZA and AMB (r = 0.47), AZA and EIL (r = 0.46), and FLC and ITC (r = 0.79). In addition, positive correlations were observed between the MIC90 values of the FLC 17-DMAG (Alvespimycin) HCl and ITC (r = 0.71). On the other hand, no significant correlations were observed between the MIC values for azoles and 24-SMTI. Some clinical isolates with a trailing effect for FLC (n = 17) and ITC (n = 11) also showed residual growth at higher concentrations of AZA (16 μg.ml-1) of 58% (10/17) and 54% (6/11) of the isolates, respectively. Residual growth was not observed in the isolates after treatment with EIL. Minimum fungicidal concentration (MFC) of AZA and EIL The MFCs obtained for half of our isolates were higher than 16 μg.ml-1, revealing a predominant fungistatic activity of the SMTI. Interestingly, 4 CNA isolates (C. glabrata, C. lusitaneae, C. zeylanoides, and C. rugosa) showed MFCs lower than 4 μg.ml-1, indicating a remarkable fungicidal activity, especially for AZA (Table 4).