Instituto de Biotecnología (IBUN), Facultad de Ciencias, Universidad Nacional de Colombia, Bogotá, 11001, Colombia.
Grupo de Investigación Celular y Molecular de Microorganismos Patógenos (CeMoP), Departamento de Ciencias Biológicas, Universidad de los Andes, Bogotá, 111711, Colombia.
Sci Rep. 2020 Mar 17;10(1):4860. doi: 10.1038/s41598-020-61729-1.
The opportunistic pathogen Malassezia pachydermatis causes bloodstream infections in preterm infants or individuals with immunodeficiency disorders and has been associated with a broad spectrum of diseases in animals such as seborrheic dermatitis, external otitis and fungemia. The current approaches to treat these infections are failing as a consequence of their adverse effects, changes in susceptibility and antifungal resistance. Thus, the identification of novel therapeutic targets against M. pachydermatis infections are highly relevant. Here, Gene Essentiality Analysis and Flux Variability Analysis was applied to a previously reported M. pachydermatis metabolic network to identify enzymes that, when absent, negatively affect biomass production. Three novel therapeutic targets (i.e., homoserine dehydrogenase (MpHSD), homocitrate synthase (MpHCS) and saccharopine dehydrogenase (MpSDH)) were identified that are absent in humans. Notably, L-lysine was shown to be an inhibitor of the enzymatic activity of MpHCS and MpSDH at concentrations of 1 mM and 75 mM, respectively, while L-threonine (1 mM) inhibited MpHSD. Interestingly, L- lysine was also shown to inhibit M. pachydermatis growth during in vitro assays with reference strains and canine isolates, while it had a negligible cytotoxic activity on HEKa cells. Together, our findings form the bases for the development of novel treatments against M. pachydermatis infections.
机会性病原体马拉色菌属导致早产儿或免疫功能障碍患者的血流感染，并与动物的一系列疾病有关，如脂溢性皮炎、外耳炎和真菌血症。由于其不良反应、敏感性变化和抗真菌耐药性，目前治疗这些感染的方法正在失败。因此，鉴定针对马拉色菌属感染的新型治疗靶点具有重要意义。在这里，基因必需性分析和通量变异性分析被应用于先前报道的马拉色菌属代谢网络，以鉴定当缺失时会对生物量产生负面影响的酶。鉴定出了三种新型治疗靶点（即同型丝氨酸脱氢酶（MpHSD）、同型柠檬酸合酶（MpHCS）和 saccharopine 脱氢酶（MpSDH）），这些酶在人类中不存在。值得注意的是，L-赖氨酸在 1mM 和 75mM 浓度下分别显示出对 MpHCS 和 MpSDH 酶活性的抑制作用，而 L-苏氨酸（1mM）抑制 MpHSD。有趣的是，L-赖氨酸还显示出在参考菌株和犬分离株的体外试验中抑制马拉色菌属生长的作用，而对 HEKa 细胞的细胞毒性作用可忽略不计。总之，我们的研究结果为开发针对马拉色菌属感染的新型治疗方法奠定了基础。
