LPC-233 (LPC233) is a highly potent and specific inhibitor of UDP-3-O-(R-3-hydroxyacyl)-N-acetylglucosamine deacetylase LpxC (Ki=8.9 pM), specifically inhibits lipid A synthesis and displays outstanding antibiotic activities.
LPC-233 is a competitive inhibitor occupying the active site and substrate binding passage against the P. aeruginosa LpxC.
LPC-233 exhihits KI value of 0.22 ± 0.06 nM and 8.9 ± 0.5 pM for the encounter complex EI and stable complex EI*, respectively.
LPC-233 is broadly effective against a clinical collection of 285 strains of Gram-negative bacterial pathogens (MIC90<1.0 ug/mL), does not display detectable antibiotic activity toward Gram-positive bacteria, such as S. aureus, at 128 μg/mL.
LPC-233 has an MIC50 value of 0.064 μg/ml and an MIC90 value of 0.125 μg/ml against 151 extended spectrum β-lactamase (ESBL)–negative, carbapenemase-negative Enterobacteriaceae isolates.
LPC-233 displays identical MIC50 and MIC90 values against 42 ESBL, carbapenemase-producing isolates that are resistant to antibiotics.
LPC-233 does not substantially inhibit human MMPs (MMP-1, MMP-2, MMP-3, MMP-7, MMP-8. MMP-9, MMP-12, MMP-13, and MMP-14) and TACE at 30 uM.
LPC-233 demonstrates in vivo efficacy in multiple murine infection models, displays no cardiovascular toxicity in vivo.