Based on DMR022 [(AEEA-Gly)2-AEEA-amphotericin B methyl ester, AEEA is the abbreviation of 8-amino-3,6-dioxaoctanoic acid] and DMR031 [(AEEA)5-amphotericin B methyl ester], DMR040 [(AEEA)2-amphotericin B methyl ester] was further designed and synthesised. Firstly, DMR040 was assessed for its antifungal activity and haemolytic toxicity with the broth dilution method and sterile defibrinated sheep blood, respectively. The minimal inhibitory concentration (MIC) of DMR040 (2 μg/mL) against Candida albicans ATCC 10231 and ATCC 90028 was reduced by 2 times compared to that of amphotericin B (1 μg/mL). No haemolysis was observed in the presence of DMR040, even at the concentration of 128 μg/mL, corresponding to 8 μg/mL AmB. Finally, the results of their efficacy assessment in mice showed that DMR040 had a 7-14 times difference compared to AmB. Furthermore, unlike DMR022 and DMR031, DMR040 had a little degree of self-association even at low concentrations in PBS, which may be a leading cause of its better biological efficacy in mice. However, DMR040 had a smaller apparent volume of distribution (Vd) and a shorter serum half-life in mice than DMR022 and amphotericin B deoxycholate (AmB-D).
© 2024. The Author(s), under exclusive licence to the Japan Antibiotics Research Association.