期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 58, 期 2, 页码 577-587出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm500955s
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资金
- Australian Research Council (ARC) [FL0992138]
- NHMRC [1027369]
- ARC [FF0668733]
- Australian Research Council [FL0992138] Funding Source: Australian Research Council
One approach to address antibiotic resistance is to develop drugs that interfere with bacterial virulence. A master regulator of virulence in Gram-negative bacteria is the oxidative folding machinery comprising DsbA and DsbB. A crystal structure at 2.5 angstrom resolution is reported here for Escherichia coli DsbA complexed with PFATCDS, a heptapeptide derived from the partner protein Escherichia coli DsbB. Details of the peptide binding mode and binding site provide valuable clues for inhibitor design. Structureactivity relationships for 30 analogues were used to produce short peptides with a cysteine that bind tightly to EcDsbA (K-d = 2.0 +/- 0.3 mu M) and inhibit its activity (IC50 = 5.1 +/- 1.1 mu M). The most potent inhibitor does not bind to or inhibit human thioredoxin that shares a similar active site. This finding suggests that small molecule inhibitors can be designed to exploit a key interaction of EcDsbA, as the basis for antivirulence agents with a novel mechanism of action.
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