Phosphonosulfonates are potent, selective inhibitors of dehydrosqualene synthase and staphyloxanthin biosynthesis in Staphylococcus aureus.
Phosphonosulfonates are potent, selective inhibitors of dehydrosqualene synthase and staphyloxanthin biosynthesis in Staphylococcus aureus.
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DOI：
10.1021/jm801023u
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发表时间：
2009-02-26
影响因子：
7.3
通讯作者：
Oldfield E
中科院分区：
文献类型：
--
作者：
Song Y;Lin FY;Yin F;Hensler M;Rodrígues Poveda CA;Mukkamala D;Cao R;Wang H;Morita CT;González Pacanowska D;Nizet V;Oldfield E
Staphylococcus aureus produces a golden carotenoid virulence factor called staphyloxanthin (STX), and we report here the inhibition of the enzyme, dehydrosqualene synthase (CrtM), responsible for the first committed step in STX biosynthesis. The most active compounds are halogen-substituted phosphonosulfonates, with Ki values as low as 5 nM against the enzyme and IC50 values for STX inhibition in S. aureus as low as 11 nM. There is, however, only a poor correlation (R2 = 0.27) between enzyme and cell pIC50 (= −log10 IC50) values. The ability to predict cell from enzyme data improves considerably (to R2 = 0.72) with addition of two more descriptors. We also investigated the activity of these compounds against human squalene synthase (SQS), as a counterscreen, finding several potent STX biosynthesis inhibitors with essentially no squalene synthase activity. These results open up the way to developing potent and selective inhibitors of an important virulence factor in S. aureus, a major human pathogen.
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影响因子：
7.3
作者：
Magnin, DR;Biller, SA;Ciosek, CP
通讯作者：
Ciosek, CP
影响因子：
7.3
作者：
Labute, P;Williams, C;Schmidt, JM
通讯作者：
Schmidt, JM
影响因子：
15
作者：
Mao, Junhong;Mukherjee, Sujoy;Oldfield, Eric
通讯作者：
Oldfield, Eric
影响因子：
2.1
作者：
GASTEIGER, J;MARSILI, M
通讯作者：
MARSILI, M
影响因子：
2.9
作者：
Rieger, CE;Lee, J;Turnbull, JL
通讯作者：
Turnbull, JL