High susceptibility of MDR and XDR Gram-negative pathogens to biphenyl-diacetylene-based difluoromethyl-allo-threonyl-hydroxamate LpxC inhibitors

J Antimicrob Chemother. 2016 Oct;71(10):2874-82. doi: 10.1093/jac/dkw210. Epub 2016 Jun 20.


Objectives: Inhibitors of uridine diphosphate-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC, which catalyses the first, irreversible step in lipid A biosynthesis) are a promising new class of antibiotics against Gram-negative bacteria. The objectives of the present study were to: (i) compare the antibiotic activities of three LpxC inhibitors (LPC-058, LPC-011 and LPC-087) and the reference inhibitor CHIR-090 against Gram-negative bacilli (including MDR and XDR isolates); and (ii) investigate the effect of combining these inhibitors with conventional antibiotics.

Methods: MICs were determined for 369 clinical isolates (234 Enterobacteriaceae and 135 non-fermentative Gram-negative bacilli). Time-kill assays with LPC-058 were performed on four MDR/XDR strains, including Escherichia coli producing CTX-M-15 ESBL and Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii producing KPC-2, VIM-1 and OXA-23 carbapenemases, respectively.

Results: LPC-058 was the most potent antibiotic and displayed the broadest spectrum of antimicrobial activity, with MIC90 values for Enterobacteriaceae, P. aeruginosa, Burkholderia cepacia and A. baumannii of 0.12, 0.5, 1 and 1 mg/L, respectively. LPC-058 was bactericidal at 1× or 2× MIC against CTX-M-15, KPC-2 and VIM-1 carbapenemase-producing strains and bacteriostatic at ≤4× MIC against OXA-23 carbapenemase-producing A. baumannii. Combinations of LPC-058 with β-lactams, amikacin and ciprofloxacin were synergistic against these strains, albeit in a species-dependent manner. LPC-058's high efficacy was attributed to the presence of the difluoromethyl-allo-threonyl head group and a linear biphenyl-diacetylene tail group.

Conclusions: These in vitro data highlight the therapeutic potential of the new LpxC inhibitor LPC-058 against MDR/XDR strains and set the stage for subsequent in vivo studies.

MeSH terms

  • Acinetobacter baumannii / drug effects
  • Amidohydrolases / antagonists & inhibitors*
  • Anti-Bacterial Agents / pharmacology*
  • Bacterial Proteins / biosynthesis
  • Drug Resistance, Multiple, Bacterial
  • Enterobacteriaceae / drug effects*
  • Enterobacteriaceae / enzymology
  • Enterobacteriaceae Infections / microbiology
  • Enzyme Inhibitors / pharmacology*
  • Escherichia coli / drug effects
  • Gram-Negative Bacteria / drug effects*
  • Gram-Negative Bacteria / enzymology
  • Gram-Negative Bacteria / pathogenicity
  • Humans
  • Hydroxamic Acids / pharmacology*
  • Klebsiella pneumoniae / drug effects
  • Microbial Sensitivity Tests
  • Pseudomonas aeruginosa / drug effects
  • Threonine / analogs & derivatives*
  • Threonine / pharmacology
  • beta-Lactamases / biosynthesis


  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Enzyme Inhibitors
  • Hydroxamic Acids
  • LPC-011
  • Threonine
  • Amidohydrolases
  • UDP-3-O-acyl-N-acetylglucosamine deacetylase
  • beta-Lactamases
  • carbapenemase