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Study · Not a test of the peptide alone · 2024

3 results

Unravelling the mechanisms causing murepavadin resistance in Pseudomonas aeruginosa: lipopolysaccharide alterations and its consequences.

Hernández-García M, Barbero-Herranz R, Bastón-Paz N, Díez-Aguilar M, López-Collazo E, Márquez-Garrido FJ, Hernández-Pérez JM, Baquero F, Ekkelenkamp MB, Fluit AC, Fuentes-Valverde V, Moscoso M and 4 more

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Bou G, Del Campo R, Cantón R, Avendaño-Ortiz J

Frontiers in cellular and infection microbiology6 Dec 2024Cited by 5 (Europe PMC)

PMID39711784 (opens in a new tab)PMCIDPMC11659217 (opens in a new tab)DOI10.3389/fcimb.2024.1446626 (opens in a new tab)PepBankPUB-39711784
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Summary

IntroductionMurepavadin is an antimicrobial peptide (AMP) in clinical development that selectively targets Pseudomonas aeruginosa LptD and whose resistance profile remains unknown. We aimed to explore genomic modifications and consequences underlying murepavadin and/or colistin susceptibility.MethodsTo define genomic mechanisms underlying resistance, we performed two approaches: 1) a genome-wide association study (GWAS) in a P. aeruginosa clinical collection (n=496), considering >0.25 mg/L as tentative cut-off of murepavadin acquired resistance; 2) a paired genomic comparison in a subset of 5 isolates and their isogenic murepavadin-resistant mutants obtained in vitro. Lipid-A composition, immunogenicity and cathelicidin and indolicidin effects on bacterial growth were also tested in this last subset of isolates. Murepavadin MICs were determined in ΔlpxL1 and ΔlpxL2 knock-out mutants obtained from a auxotroph PAO1 derivative.ResultsGWAS revealed a missense variant (A→G p.Thr260Ala in the hisJ gene) associated with murepavadin resistance although both resistant and susceptible strains harbored it (21% and 12% respectively, OR=1.92, p=0.012 in χ² test). Among the isolate subset, murepavadin-resistant mutants with deletions in lpxL1 and lpxL2 genes showed lower abundance of hexa-acylated lipid-A (m/z 1616, 1632). 4-aminoarabinose addition was found only in colistin-resistant isolates but not in the other ones, irrespective of murepavadin susceptibility. Accordingly, ΔlpxL1 and ΔlpxL2 mutants exhibited higher murepavadin MICs than parental PAO1 auxotroph strain (2 and 4 vs 0.5 mg/L respectively). Lipopolysaccharide from murepavadin-resistant mutants triggered lower inflammatory responses in human monocytes. Those with lpxL mutations and hexa-acylated lipid-A loss also exhibited greater growth reduction when exposed to host-derived AMPs cathelicidin and indolicidin.DiscussionHigh murepavadin-resistance seems to be linked to lpxL1 and lpxL2 mutations and lower hexa-acylated lipid-A, corresponding to lower inflammatory induction and higher susceptibility to host-derived AMPs. Although GWAS identified one variant associated with the murepavadin-resistant phenotype, data revealed that there was no unique single genetic event underlying this phenotype. Our study provides insight into the mechanisms underlying murepavadin susceptibility.
CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study3

No result from this study comes from a test of the peptide.

Studies that did not test the peptide alone3

In this study, Murepavadin was a lab tool or a carrier, part of a mix, or the subject of a lab method. These results are not evidence about taking Murepavadin.

  1. 01LabNot a test of Murepavadin aloneIn vitro (cells)Mechanism

    In bacterial isolates, the hisJ variant was associated with murepavadin resistance (OR=1.92, p=0.012).

    In plain wordsIn lab tests, a hisJ variant was linked to murepavadin resistance.

    Peptide
    Murepavadin
    Outcome
    IncreasehisJ variant association with resistance
    Study

    Pseudomonas aeruginosan = 496

    Clinical Pseudomonas aeruginosa collection
    Outcome group
    Infection and antimicrobial activity · Infection

    Source sentences

    Summary
    GWAS revealed a missense variant (A→G p.Thr260Ala in the hisJ gene) associated with murepavadin resistance although both resistant and susceptible strains harbored it (21% and 12% respectively, OR=1.92, p=0.012 in χ² test).
    1 context sentence
    Summary · context
    To define genomic mechanisms underlying resistance, we performed two approaches: 1) a genome-wide association study (GWAS) in a P. aeruginosa clinical collection (n=496), considering >0.25 mg/L as tentative cut-off of murepavadin acquired resistance;

    In this study, Murepavadin was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Murepavadin.

  2. 02LabNot a test of Murepavadin aloneIn vitro (cells)Mechanism

    In bacteria, lpxL1 knockout increased murepavadin MIC to 2 mg/L versus 0.5 mg/L in the parental strain.

    In plain wordsIn lab tests, lpxL1 knockout increased murepavadin MIC compared with the parental strain.

    Peptide
    Murepavadin
    Outcome
    IncreaselpxL1 knockout MIC
    Study

    Pseudomonas aeruginosan: not reported in source

    Clinical isolates and bacterial mutants
    Comparator
    Parental PAO1 auxotroph strain
    Outcome group
    Infection and antimicrobial activity · Infection

    Measurements

    MIC
    2 mg/L
    lpxL1 knockout
    MIC
    0.5 mg/L
    parental strain

    Source sentences

    Summary
    Accordingly, ΔlpxL1 and ΔlpxL2 mutants exhibited higher murepavadin MICs than parental PAO1 auxotroph strain (2 and 4 vs 0.5 mg/L respectively).

    In this study, Murepavadin was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Murepavadin.

  3. 03LabNot a test of Murepavadin aloneIn vitro (cells)Mechanism

    In bacteria, lpxL2 knockout increased murepavadin MIC to 4 mg/L versus 0.5 mg/L in the parental strain.

    In plain wordsIn lab tests, lpxL2 knockout increased murepavadin MIC compared with the parental strain.

    Peptide
    Murepavadin
    Outcome
    IncreaselpxL2 knockout MIC
    Study

    Pseudomonas aeruginosan: not reported in source

    Clinical isolates and bacterial mutants
    Comparator
    Parental PAO1 auxotroph strain
    Outcome group
    Infection and antimicrobial activity · Infection

    Measurements

    MIC
    4 mg/L
    lpxL2 knockout
    MIC
    0.5 mg/L
    parental strain

    Source sentences

    Summary
    Accordingly, ΔlpxL1 and ΔlpxL2 mutants exhibited higher murepavadin MICs than parental PAO1 auxotroph strain (2 and 4 vs 0.5 mg/L respectively).

    In this study, Murepavadin was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Murepavadin.

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

  1. Version 2Current

    27 Oct 2026, 18:20 UTC

    Study results updated

  2. Version 1

    27 Oct 2026, 16:32 UTC

    First added · source update from Europe PMC

Subjects

Terms as the source lists them.

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