title: High susceptibility of MDR and XDR Gram-negative pathogens to biphenyl-diacetylene-based difluoromethyl-allo-threonyl-hydroxamate LpxC inhibitors.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Univ. Lille, CNRS, INSERM, CHU Lille, U1019-UMR 8204, Center for Infection and Immunity of Lille, F-59000 Lille, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Titecat
authors.affiliation: Department of Chemistry, Duke University, Durham, NC 27708, USA.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Liang
authors.affiliation: Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Chul-Jin
authors.initials: CJ
authors.lastname: Lee
authors.affiliation: Univ. Lille, CNRS, INSERM, CHU Lille, U1019-UMR 8204, Center for Infection and Immunity of Lille, F-59000 Lille, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Charlet
authors.affiliation: UMR CNRS 6249, Chrono-environnement, Université de Bourgogne-Franche-Comté, Centre de Ressources Biologiques Ferdinand Cabanne, Hygiène Hospitalière, CHU Besançon, F-25000 Besançon, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Hocquet
authors.affiliation: EA 4043 Unité Bactéries Pathogènes et Santé (UBaPS), Univ. Paris-Sud, Unité Paris Saclay, F-92290 Châtenay-Malabry, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Lambert
authors.affiliation: UMR-MD1, Aix Marseille Université, Institut de Recherche Biomédicale des Armées, F-13000 Marseille, France.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Pagès
authors.affiliation: Univ. Lille, CNRS, INSERM, CHU Lille, U1019-UMR 8204, Center for Infection and Immunity of Lille, F-59000 Lille, France.
authors.forename: René
authors.initials: R
authors.lastname: Courcol
authors.affiliation: Univ. Lille, CNRS, INSERM, CHU Lille, U1019-UMR 8204, Center for Infection and Immunity of Lille, F-59000 Lille, France.
authors.forename: Florent
authors.initials: F
authors.lastname: Sebbane
authors.affiliation: Department of Chemistry, Duke University, Durham, NC 27708, USA Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Toone
authors.affiliation: Department of Chemistry, Duke University, Durham, NC 27708, USA Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Pei
authors.initials: P
authors.lastname: Zhou
authors.affiliation: Univ. Lille, CNRS, INSERM, CHU Lille, U1019-UMR 8204, Center for Infection and Immunity of Lille, F-59000 Lille, France nadine.lemaitre@chru-lille.fr.
authors.forename: Nadine
authors.initials: N
authors.lastname: Lemaitre
mesh_terms: D040981:Acinetobacter baumannii / Q000187:drug effects; D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000096:biosynthesis; D024901:Drug Resistance, Multiple, Bacterial; D004755:Enterobacteriaceae / Q000187:drug effects* / Q000201:enzymology; D004756:Enterobacteriaceae Infections / Q000382:microbiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects; D006090:Gram-Negative Bacteria / Q000187:drug effects* / Q000201:enzymology / Q000472:pathogenicity; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007711:Klebsiella pneumoniae / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D013912:Threonine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001618:beta-Lactamases / Q000096:biosynthesis
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; C000609007:LPC-011; D013912:Threonine; D000581:Amidohydrolases; C097307:UDP-3-O-acyl-N-acetylglucosamine deacetylase; D001618:beta-Lactamases; C063912:carbapenemase