α‑Amino Diphenyl Phosphonates as Novel Inhibitors of Escherichia coli ClpP Protease

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.