Mandala S M, Thornton R A, Milligan J, Rosenbach M, Garcia-Calvo M, Bull H G, Harris G, Abruzzo G K, Flattery A M, Gill C J, Bartizal K, Dreikorn S, Kurtz M B
Department of Biochemistry, Merck Research Laboratories, Rahway, New Jersey 07065, USA.
J Biol Chem. 1998 Jun 12;273(24):14942-9. doi: 10.1074/jbc.273.24.14942.
Rustmicin is a 14-membered macrolide previously identified as an inhibitor of plant pathogenic fungi by a mechanism that was not defined. We discovered that rustmicin inhibits inositol phosphoceramide synthase, resulting in the accumulation of ceramide and the loss of all of the complex sphingolipids. Rustmicin has potent fungicidal activity against clinically important human pathogens that is correlated with its sphingolipid inhibition. It is especially potent against Cryptococcus neoformans, where it inhibits growth and sphingolipid synthesis at concentrations <1 ng/ml and inhibits the enzyme with an IC50 of 70 pM. This inhibition of the membrane-bound enzyme is reversible; moreover, rustmicin is nearly equipotent against the solubilized enzyme. Rustmicin was efficacious in a mouse model for cryptococcosis, but it was less active than predicted from its in vitro potency against this pathogen. Stability and drug efflux were identified as two factors limiting rustmicin's activity. In the presence of serum, rustmicin rapidly epimerizes at the C-2 position and is converted to a gamma-lactone, a product that is devoid of activity. Rustmicin was also found to be a remarkably good substrate for the Saccharomyces cerevisiae multidrug efflux pump encoded by PDR5.
锈霉素是一种14元大环内酯类化合物，先前被鉴定为植物致病真菌的抑制剂，但其作用机制尚未明确。我们发现锈霉素可抑制肌醇磷酸神经酰胺合酶，导致神经酰胺积累以及所有复合鞘脂类物质的缺失。锈霉素对临床上重要的人类病原体具有强大的杀菌活性，这与其对鞘脂类物质的抑制作用相关。它对新型隐球菌尤为有效，在浓度<1 ng/ml时就能抑制其生长和鞘脂类物质合成，对该酶的半数抑制浓度（IC50）为70 pM。这种对膜结合酶的抑制作用是可逆的；此外，锈霉素对溶解状态的酶几乎具有同等效力。锈霉素在小鼠隐球菌病模型中有效，但活性低于根据其体外对该病原体的效力所预测的水平。稳定性和药物外排被确定为限制锈霉素活性的两个因素。在血清存在的情况下，锈霉素在C-2位迅速发生差向异构化，并转化为γ-内酯，该产物没有活性。锈霉素还被发现是由PDR5编码的酿酒酵母多药外排泵的一个非常好的底物。
