Specific interactions between the Candida albicans ABC transporter Cdr1p ectodomain and a D-octapeptide derivative inhibitor.
Specific interactions between the Candida albicans ABC transporter Cdr1p ectodomain and a D-octapeptide derivative inhibitor.
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DOI：
10.1111/j.1365-2958.2012.08140.x
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发表时间：
2012-08
影响因子：
3.6
通讯作者：
Monk BC
中科院分区：
文献类型：
--
作者：
Niimi K;Harding DR;Holmes AR;Lamping E;Niimi M;Tyndall JD;Cannon RD;Monk BC
白色念珠菌atp结合盒转运体CaCdr1p的过度表达导致对氟康唑（FLC）等唑类药物的临床显著耐药。筛选了一个约1.89 × 106个成员的d-八肽组合文库，将文库成员集中在酵母细胞表面，鉴定出d-八肽d-NH2-FFKWQRRR-CONH2的4-甲氧基-2,3,6-三甲基苯硫基衍生物RC21v3是一种有效的立体特异性抑制剂。RC21v3使过表达CaCdr1p而不表达其他真菌ABC转运体、白色念珠菌MFS转运体CaMdr1p或唑靶酶CaErg11p的酿酒酵母菌对FLC化学致敏。RC21v3也使过表达CaCDR1的临床白色念珠菌分离株对FLC化学致敏，即使CaCDR2过表达。通过表达CaCdr1p的酿酒葡萄球菌自发的RC21v3耐药抑制突变体证实了RC21v3对CaCdr1p的特异性靶向作用。抑制基因突变在CaCdr1p胞外环1、3、4和6的旁边或内部引入了一个正电荷，或者在跨膜段5的胞外质端附近引入了一个芳香残基。突变不影响CaCdr1p定位或Cdr1p atp酶活性，但增加了对CaCdr1p底物FLC、罗丹明6G、罗丹明123和环己亚胺的易感性。抑制基因突变表明类似药物的CaCdr1p抑制剂FK506、enniatin、milbemycin α11和milbemycin β9具有与RC21v3相似的作用方式。
Over-expression of the Candida albicans ATP-binding cassette transporter CaCdr1p causes clinically significant resistance to azole drugs including fluconazole (FLC). Screening of a ~1.89 × 106 member d-octapeptide combinatorial library that concentrates library members at the yeast cell surface identified RC21v3, a 4-methoxy-2,3,6-trimethylbenzenesulphonyl derivative of the d-octapeptide d-NH2-FFKWQRRR-CONH2, as a potent and stereospecific inhibitor of CaCdr1p. RC21v3 chemosensitized Saccharomyces cerevisiae strains over-expressing CaCdr1p but not other fungal ABC transporters, the C. albicans MFS transporter CaMdr1p or the azole target enzyme CaErg11p, to FLC. RC21v3 also chemosensitized clinical C. albicans isolates over-expressing CaCDR1 to FLC, even when CaCDR2 was over-expressed. Specific targeting of CaCdr1p by RC21v3 was confirmed by spontaneous RC21v3 chemosensitization resistant suppressor mutants of S. cerevisiae expressing CaCdr1p. The suppressor mutations introduced a positive charge beside, or within, extracellular loops 1, 3, 4 and 6 of CaCdr1p or an aromatic residue near the extracytoplasmic end of transmembrane segment 5. The mutations did not affect CaCdr1p localization or Cdr1p ATPase activity but some increased susceptibility to the CaCdr1p substrates FLC, rhodamine 6G, rhodamine 123 and cycloheximide. The suppressor mutations showed that the drug-like CaCdr1p inhibitors FK506, enniatin, milbemycin α11 and milbemycin β9 have modes of action similar to RC21v3.
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影响因子：
3
作者：
Lamping, Erwin;Baret, Philippe V.;Holmes, Ann R.;Monk, Brian C.;Goffeau, Andre;Cannon, Richard D.
通讯作者：
Cannon, Richard D.
影响因子：
3.6
作者：
Egner, R;Bauer, BE;Kuchler, K
通讯作者：
Kuchler, K
影响因子：
2.9
作者：
Hanson, L;May, L;Golin, J
通讯作者：
Golin, J
影响因子：
4.8
作者：
Kolaczkowski, M;vanderRest, M;Goffeau, A
通讯作者：
Goffeau, A
影响因子：
4.9
作者：
Albertson, GD;Niimi, M;Jenkinson, HF
通讯作者：
Jenkinson, HF