Characterization of echinocandin-resistant mutants of Candida albicans: genetic, biochemical, and virulence studies
Characterization of echinocandin-resistant mutants of Candida albicans: genetic, biochemical, and virulence studies
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白色念珠菌抗棘白菌素突变体的表征：遗传、生化和毒力研究
作者：
Myra B. Kurtz;G. Abruzzo;A. Flattery;Kenneth F. Bartizal;J. Marrinan;W. Li;James A. Milligan;K. Nollstadt;C. Douglas
肺白菌素是棘白菌素类的有效抗真菌剂，其正在开发用作广谱抗真菌治疗。对于治疗严重真菌感染的任何新治疗类别，一个重要的考虑因素是耐药性发展的可能性。在这项研究中，我们已经分离和表征了四个独立的自发性白念珠菌突变体，对强效半合成的肺念珠菌L-733，560具有抗性。这些突变体具有酿酒酵母的FKS 1/ETG 1棘白菌素抗性突变体的许多特性，包括（i）对其它1，3-β-D-葡聚糖合酶抑制剂（如丘疹菌素和棘白菌素）的交叉抗性，但对其它抗真菌剂的敏感性没有变化;（ii）体外葡聚糖合酶活性比野生型亲本酶对肺白菌素更具抗性;和（iii）原生质球融合株的半显性耐药性。将突变株与C.通过L. Beckford和D. Kerridge（突变体M-2）（摘要PS3.11，在Proceedings of the XI Congress of the International Society for Human and Animal Mycology，Montreal，Canada，1992）和A.卡索恩河E. Mason和D. Kerridge（突变体CA-2）（Sabouraudia 19：97-110，1981）。所有菌株在体外均具有抗性酶活性。M-2生长不良，酶活性低。相比之下，CA-2和自发突变体的生长以及父母和葡聚糖合酶活性的正常水平。这些结果表明，这些抗性突变体可能具有葡聚糖合酶的改变。CA-2不能形成芽管，这是自发突变体保留的能力。在播散性念珠菌病小鼠模型中，自发突变株的毒力未受损，而M-2和CA-2的毒力比其亲本菌株低2个数量级。值得注意的是，用自发突变体CAI 4 R1激发的小鼠对较低水平的L-733，560的治疗反应比通过体外易感性增加所预测的要低。
The pneumocandins are potent antifungal agents of the echinocandin class which are under development for use as broad-spectrum antimycotic therapy. One important consideration for any new therapeutic class for treating serious fungal infections is the potential for drug resistance development. In this study we have isolated and characterized four independent spontaneous Candida albicans mutants resistant to the potent semisynthetic pneumocandin L-733,560. These mutants have many of the properties of FKS1/ETG1 echinocandin-resistant mutants of Saccharomyces cerevisiae, including (i) cross-resistance to other 1,3-beta-D-glucan synthase inhibitors, such as papulacandin and echinocandins, but no change in sensitivity to other antifungal agents; (ii) in vitro glucan synthase activity that is more resistant to pneumocandins than the wild-type parent enzyme; and (iii) semidominant drug resistance in spheroplast fusion strains. The mutants were compared with C. albicans echinocandin-resistant mutants isolated by mutagenesis by L. Beckford and D. Kerridge (mutant M-2) (abstr. PS3.11, in Proceedings of the XI Congress of the International Society for Human and Animal Mycology, Montreal, Canada, 1992) and by A. Cassone, R. E. Mason, and D. Kerridge (mutant CA-2) (Sabouraudia 19:97-110, 1981). All of the strains had resistant enzyme activity in vitro. M-2 grew poorly and had low levels of enzyme activity. In contrast, CA-2 and the spontaneous mutants grew as well as the parents and had normal levels of glucan synthase activity. These results suggest that these resistant mutants may have alterations in glucan synthase. CA-2 was unable to form germ tubes, an ability retained by the spontaneous mutants. The virulence of the spontaneous mutants was unimpaired in a mouse model of disseminated candidiasis, while M-2 and CA-2 were 2 orders of magnitude less virulent than their parent strains. Significantly, mice challenged with the spontaneous mutant CAI4R1 responded therapeutically to lower levels of L-733,560 than would he predicted by the increase in in vitro susceptibility.
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影响因子：
3.3
作者：
D. Irwin;W. Fonzi;D. Ho;S. Sag
通讯作者：
D. Irwin;W. Fonzi;D. Ho;S. Sag
DOI：
10.1073/pnas.91.13.6216
发表时间：
1994-06-21
影响因子：
11.1
作者：
GOW, NAR;ROBBINS, PW;KINSMAN, OS
通讯作者：
KINSMAN, OS
白色念珠菌原养型自然变种的遗传分析。
影响因子：
3.3
作者：
Goshorn,AK;Scherer,S
通讯作者：
Scherer,S
影响因子：
158.5
作者：
WINGARD, JR;MERZ, WG;SARAL, R
通讯作者：
SARAL, R