Evidence map›Paper›PMID 37432123›Full record

ArticleMicrobiology spectrum2023

Lipid A Modification and Metabolic Adaptation in Polymyxin-Resistant, New Delhi Metallo-β-Lactamase-Producing Klebsiella pneumoniae.

Jing Lu, Meiling Han, Heidi H Yu, Phillip J Bergen, Yiyun Liu, Jinxin Zhao, Hasini Wickremasinghe, Xukai Jiang, Yang Hu, Haiyan Du and 2 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Microbiology spectrum, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.

0numbers the graph read from it
0cells of the map it votes in
7citing papers in PubMed
0.8field-weighted citation impact, top 35% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

7 citing papers in PubMed, 8 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

12 authors at 3 institutions in 2 countries.

Jing Lu *Infection Program, Department of Microbiology, Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia.ORCID 0000-0002-5834-7942
Meiling Han *Infection Program, Department of Microbiology, Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia.ORCID 0000-0002-0861-2437
Heidi H YuInfection Program, Department of Microbiology, Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia.
Phillip J BergenInfection Program, Department of Microbiology, Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia.
Yiyun LiuNational Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, College of Veterinary Medicine, South China Agricultural University, Guangzhou, Guangdong, China.
Jinxin ZhaoInfection Program, Department of Microbiology, Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia.
Hasini WickremasingheInfection Program, Department of Microbiology, Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia.
Xukai JiangInfection Program, Department of Microbiology, Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia.
Yang HuInfection Program, Department of Microbiology, Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia.
Haiyan DuInfection Program, Department of Microbiology, Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia.
Yan ZhuInfection Program, Department of Microbiology, Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia.ORCID 0000-0001-7342-3782
Tony VelkovDepartment of Pharmacology, The Faculty of Medicine Nursing and Health Sciences, Monash University, Melbourne, Victoria, Australia.
Australian Regenerative Medicine Institute · AUMonash University · AUSouth China Agricultural University · CN

Funding

Targeting the Urgent Need for New Antibiotics against Gram-negative ‘Superbugs’R01AI132154 · NIAID · MONASH UNIVERSITY · PI LI, JIAN, VELKOV, TONY · 2017 to 2021
$4.3M
Development of a broad spectrum teixobactin-lipopeptide hybrid for the treatment of lung infections caused by pan-drug resistant ‘superbugs’R01AI170889 · NIAID · UNIV OF NORTH CAROLINA CHAPEL HILL · PI MALONEY, SARA ELIZABETH, RAO, GAURI G · 2022 to 2025
$3.8M
Pharmacology of intrathecal/intraventricular polymyxins: A systems-based approachR01AI146241 · NIAID · UNIV OF NORTH CAROLINA CHAPEL HILL · PI RAO, GAURI G, VELKOV, TONY · 2019 to 2023
$3.0M
NIAID NIH HHS R01 AI132154NIAID NIH HHS R01 AI146241NIAID NIH HHS R01 AI170889
6 · The paper itself

Abstract

Polymyxins are last-line antibiotics employed against multidrug-resistant (MDR) Klebsiella pneumoniae. Worryingly, polymyxin resistance is rapidly on the rise globally. Polymyxins initially target lipid A of lipopolysaccharides (LPSs) in the cell outer membrane (OM), causing disorganization and cell lysis. While most studies focus on how genetic variations confer polymyxin resistance, the mechanisms of membrane remodeling and metabolic changes in polymyxin-resistant strains remain unclear, thus hampering the development of effective therapies to treat severe K. pneumoniae infections. In the present study, lipid A profiling, OM lipidomics, genomics, and metabolomics were integrated to elucidate the global mechanisms of polymyxin resistance and metabolic adaptation in a polymyxin-resistant strain (strain S01R; MIC of >128 mg/L) obtained from K. pneumoniae strain S01, a polymyxin-susceptible (MIC of 2 mg/L), New Delhi metallo-β-lactamase (NDM)-producing MDR clinical isolate. Genomic analysis revealed a novel in-frame deletion at position V258 of PhoQ in S01R, potentially leading to lipid A modification with 4-amino-4-deoxy-l-arabinose (L-Ara4N) despite the absence of polymyxin B. Comparative metabolomic analysis revealed slightly elevated levels of energy production and amino acid metabolism in S01R compared to their levels in S01. Exposure to polymyxin B (4 mg/L for S01 and 512 mg/L for S01R) substantially altered energy, nucleotide, and amino acid metabolism and resulted in greater accumulation of lipids in both strains. Furthermore, the change induced by polymyxin B treatment was dramatic at both 1 and 4 h in S01 but only significant at 4 h in S01R. Overall, profound metabolic adaptation was observed in S01R following polymyxin B treatment. These findings contribute to our understanding of polymyxin resistance mechanisms in problematic NDM-producing K. pneumoniae strains and may facilitate the discovery of novel therapeutic targets.

Indexed as

Klebsiella InfectionsPolymyxinsAnti-Bacterial Agentsbeta-LactamasesHumansKlebsiella pneumoniaeLipid ALipid MetabolismMicrobial Sensitivity TestsPolymyxin BAnti-Bacterial Agentsbeta-lactamase NDM-1beta-LactamasesLipid APolymyxin BPolymyxinsKlebsiella pneumoniaelipid A modificationlipidomicsmetabolomicsphoQpolymyxin

Identifiers

PMID37432123
PMCPMC10433984
OpenAlexW4383872706

What OpenQuestion holds

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LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.