jm8b01466_si_002.csv (17.1 kB)
α‑Amino Diphenyl Phosphonates as Novel Inhibitors of Escherichia coli ClpP Protease
datasetposted on 2018-12-20, 00:00 authored by Carlos Moreno-Cinos, Elisa Sassetti, Irene G. Salado, Gesa Witt, Siham Benramdane, Laura Reinhardt, Cristina D. Cruz, Jurgen Joossens, Pieter Van der Veken, Heike Brötz-Oesterhelt, Päivi Tammela, Mathias Winterhalter, Philip Gribbon, Björn Windshügel, Koen Augustyns
Increased Gram-negative bacteria resistance to antibiotics is becoming a global problem, and new classes of antibiotics with novel mechanisms of action are required. The caseinolytic protease subunit P (ClpP) is a serine protease conserved among bacteria that is considered as an interesting drug target. ClpP function is involved in protein turnover and homeostasis, stress response, and virulence among other processes. The focus of this study was to identify new inhibitors of Escherichia coli ClpP and to understand their mode of action. A focused library of serine protease inhibitors based on diaryl phosphonate warheads was tested for ClpP inhibition, and a chemical exploration around the hit compounds was conducted. Altogether, 14 new potent inhibitors of E. coli ClpP were identified. Compounds 85 and 92 emerged as most interesting compounds from this study due to their potency and, respectively, to its moderate but consistent antibacterial properties as well as the favorable cytotoxicity profile.
chemical explorationCompounds 85stress responseserine protease inhibitorsClpP functionnovel mechanismsNovel Inhibitorsdiaryl phosphonate warheadsClpP inhibitionEscherichia coli ClpPcoli ClpPprotein turnovercytotoxicity profilecaseinolytic protease subunit PGram-negative bacteria resistancedrug targetserine proteaseEscherichia coli ClpP Protease