Zhang Jinhua, Xu Hongjiang, Dong Yuanzhen, Li Ruifang, Feng Jun
School of Biological Engineering Henan University of Technology, Zhengzhou, Henan, China.
Shanghai Duomirui Biotechnology Ltd., Shanghai, China.
J Antibiot (Tokyo). 2025 Feb;78(3):203-208. doi: 10.1038/s41429-024-00804-5. Epub 2025 Jan 6.
Based on DMR022 [(AEEA-Gly)-AEEA-amphotericin B methyl ester, AEEA is the abbreviation of 8-amino-3,6-dioxaoctanoic acid] and DMR031 [(AEEA)-amphotericin B methyl ester], DMR040 [(AEEA)-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).
基于DMR022 [（AEEA-甘氨酸）-AEEA-两性霉素B甲酯，AEEA是8-氨基-3,6-二氧杂辛酸的缩写]和DMR031 [（AEEA）-两性霉素B甲酯]，进一步设计并合成了DMR040 [（AEEA）-两性霉素B甲酯]。首先，分别采用肉汤稀释法和无菌去纤维蛋白羊血对DMR040的抗真菌活性和溶血毒性进行了评估。DMR040（2μg/mL）对白色念珠菌ATCC 10231和ATCC 90028的最小抑菌浓度（MIC）与两性霉素B（1μg/mL）相比降低了2倍。即使在浓度为128μg/mL（相当于8μg/mL两性霉素B）时，在DMR040存在的情况下也未观察到溶血现象。最后，它们在小鼠体内的疗效评估结果表明，DMR040与两性霉素B相比有7至14倍的差异。此外，与DMR022和DMR031不同，即使在PBS中低浓度下，DMR040也有一定程度的自缔合，这可能是其在小鼠体内具有更好生物学疗效的主要原因。然而，与DMR022和两性霉素B脱氧胆酸盐（AmB-D）相比，DMR040在小鼠体内的表观分布容积（Vd）较小，血清半衰期较短。
