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Octapeptin C4 and polymyxin resistance occur via distinct pathways in an epidemic XDRKlebsiella pneumoniaeST258 isolate
- Source :
- Journal of Antimicrobial Chemotherapy. 74:582-593
- Publication Year :
- 2018
- Publisher :
- Oxford University Press (OUP), 2018.
-
Abstract
- BACKGROUND: Polymyxin B and E (colistin) have been pivotal in the treatment of XDR Gram-negative bacterial infections; however, resistance has emerged. A structurally related lipopeptide, octapeptin C4, has shown significant potency against XDR bacteria, including polymyxin-resistant strains, but its mode of action remains undefined. OBJECTIVES: We sought to compare and contrast the acquisition of resistance in an XDR Klebsiella pneumoniae (ST258) clinical isolate in vitro with all three lipopeptides to potentially unveil variations in their mode of action. METHODS: The isolate was exposed to increasing concentrations of polymyxins and octapeptin C4 over 20 days. Day 20 strains underwent WGS, complementation assays, antimicrobial susceptibility testing and lipid A analysis. RESULTS: Twenty days of exposure to the polymyxins resulted in a 1000-fold increase in the MIC, whereas for octapeptin C4 a 4-fold increase was observed. There was no cross-resistance observed between the polymyxin- and octapeptin-resistant strains. Sequencing of polymyxin-resistant isolates revealed mutations in previously known resistance-associated genes, including crrB, mgrB, pmrB, phoPQ and yciM, along with novel mutations in qseC. Octapeptin C4-resistant isolates had mutations in mlaDF and pqiB, genes related to phospholipid transport. These genetic variations were reflected in distinct phenotypic changes to lipid A. Polymyxin-resistant isolates increased 4-amino-4-deoxyarabinose fortification of lipid A phosphate groups, whereas the lipid A of octapeptin C4-resistant strains harboured a higher abundance of hydroxymyristate and palmitoylate. CONCLUSIONS: Octapeptin C4 has a distinct mode of action compared with the polymyxins, highlighting its potential as a future therapeutic agent to combat the increasing threat of XDR bacteria.
- Subjects :
- 0301 basic medicine
Microbiology (medical)
medicine.drug_class
Klebsiella pneumoniae
Polymyxin
030106 microbiology
Microbial Sensitivity Tests
Peptides, Cyclic
Microbiology
Lipopeptides
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Drug Resistance, Multiple, Bacterial
medicine
Humans
Pharmacology (medical)
030212 general & internal medicine
Polymyxin B
Original Research
Pharmacology
Antiinfective agent
Whole Genome Sequencing
biology
Colistin
Lipopeptide
Phospholipid transport
biology.organism_classification
Anti-Bacterial Agents
Klebsiella Infections
Multiple drug resistance
Infectious Diseases
chemistry
Mutation
lipids (amino acids, peptides, and proteins)
medicine.drug
Subjects
Details
- ISSN :
- 14602091 and 03057453
- Volume :
- 74
- Database :
- OpenAIRE
- Journal :
- Journal of Antimicrobial Chemotherapy
- Accession number :
- edsair.doi.dedup.....84f0ceb61a27c6076d90f55e3ebe5f89