Medicinal Chemistry, Mutabilis, 102 Avenue Gaston Roussel, 93230 Romainville, France.
J Med Chem. 2013 Feb 28;56(4):1418-30. doi: 10.1021/jm301499r. Epub 2013 Feb 14.
We report here the optimization of an HldE kinase inhibitor to low nanomolar potency, which resulted in the identification of the first reported compounds active on selected E. coli strains. One of the most interesting candidates, compound 86, was shown to inhibit specifically bacterial LPS heptosylation on efflux pump deleted E. coli strains. This compound did not interfere with E. coli bacterial growth (MIC > 32 μg/mL) but sensitized this pathogen to hydrophobic antibiotics like macrolides normally inactive on Gram-negative bacteria. In addition, 86 could sensitize E. coli to serum complement killing. These results demonstrate that HldE kinase is a suitable target for drug discovery. They also pave the way toward novel possibilities of treating or preventing bloodstream infections caused by pathogenic Gram negative bacteria by inhibiting specific virulence factors.
我们在此报告 HldE 激酶抑制剂优化至纳摩尔效力的研究结果，这导致了首批针对选定大肠杆菌菌株具有活性的报告化合物的鉴定。其中最有趣的候选物之一是化合物 86，它被证明可特异性抑制外排泵缺失的大肠杆菌菌株上的 LPS 七糖基化。该化合物不干扰大肠杆菌的细菌生长（MIC > 32 μg/mL），但使该病原体对疏水性抗生素（如大环内酯类抗生素）敏感，而这些抗生素通常对革兰氏阴性菌无效。此外，86 可以使大肠杆菌对血清补体杀伤敏感。这些结果表明 HldE 激酶是药物发现的合适靶标。它们还为通过抑制特定的毒力因子来治疗或预防由致病性革兰氏阴性菌引起的血流感染开辟了新的可能性。
