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High susceptibility of MDR and XDR Gram-negative pathogens to biphenyl-diacetylene-based difluoromethyl-allo-threonyl-hydroxamate LpxC inhibitors
- Source :
- Journal of Antimicrobial Chemotherapy, Journal of Antimicrobial Chemotherapy, Oxford University Press (OUP), 2016, 71 (10), pp.2874-82. 〈10.1093/jac/dkw210〉, Journal of Antimicrobial Chemotherapy, Oxford University Press (OUP), 2016, 71 (10), pp.2874-82. ⟨10.1093/jac/dkw210⟩, Journal of Antimicrobial Chemotherapy, 2016, 71 (10), pp.2874-82. ⟨10.1093/jac/dkw210⟩
- Publication Year :
- 2016
- Publisher :
- Oxford University Press (OUP), 2016.
-
Abstract
- International audience; 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.MethodsMICs 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.ResultsLPC-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.ConclusionsThese 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.
- Subjects :
- Acinetobacter baumannii
Threonine
0301 basic medicine
Microbiology (medical)
Klebsiella pneumoniae
medicine.drug_class
030106 microbiology
Antibiotics
Microbial Sensitivity Tests
Hydroxamic Acids
medicine.disease_cause
beta-Lactamases
Amidohydrolases
Microbiology
03 medical and health sciences
Bacterial Proteins
Enterobacteriaceae
[ SDV.MP ] Life Sciences [q-bio]/Microbiology and Parasitology
Drug Resistance, Multiple, Bacterial
Gram-Negative Bacteria
Escherichia coli
polycyclic compounds
medicine
Humans
Pharmacology (medical)
Enzyme Inhibitors
Original Research
Pharmacology
biology
Pseudomonas aeruginosa
Enterobacteriaceae Infections
biochemical phenomena, metabolism, and nutrition
bacterial infections and mycoses
Antimicrobial
biology.organism_classification
Anti-Bacterial Agents
3. Good health
Ciprofloxacin
[SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology
Infectious Diseases
Amikacin
lipids (amino acids, peptides, and proteins)
medicine.drug
Subjects
Details
- ISSN :
- 14602091 and 03057453
- Volume :
- 71
- Database :
- OpenAIRE
- Journal :
- Journal of Antimicrobial Chemotherapy
- Accession number :
- edsair.doi.dedup.....4b1981a6aafeb94092376df4222d2d4f