Adaptive Responses of
            <i>Pseudomonas aeruginosa</i>
            to Treatment with Antibiotics

Wüllner, Dominik; Gesper, Maren; Haupt, Annika; Liang, Xiaofei; Zhou, Pei; Dietze, Pascal; Narberhaus, Franz; Bandow, Julia E.

doi:10.1128/aac.00878-21

Cited by 9 publications

(10 citation statements)

References 72 publications

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“…This proteolysisindependent strategy ensures a synchronized synthesis of cell envelope components. Consistent with that finding, CHIR-090 treatment in P. aeruginosa induced GlmU, which provides UDP-GlcNAc, the common precursor of LPS and peptidoglycan synthesis (45). This does not exclude a regulatory interconnection between LPS and PL biosynthesis in P. aeruginosa.…”

Section: Species-specific Responses To Lpxc Inhibitors In Gram-negati...supporting

confidence: 50%

“…Like many other antimicrobial compounds (44), the LpxC inhibitors seem to be exported by multi-drug efflux pumps. This was also shown to be case for CHIR-090 in P. aeruginosa (45,46).…”

Section: Similar Yet Different Responses Of E Coli To Lpxc Inhibitionmentioning

confidence: 52%

“…Treated bacteria probably tried to combat growth limitation by an enhanced uptake of amino acids by proteins like HisJ or TcyJ. Another hint for a global metabolic shutdown was the CHIR-090-induced increase of DksA, which was also regulated in P. aeruginosa in response to CHIR-090 exposure (45). DksA is a transcriptional regulator that synergistically binds together with the alarmone ppGpp to RNA polymerase, thereby modulating gene expression in response to amino acid starvation (58).…”

Section: Similar Yet Different Responses Of E Coli To Lpxc Inhibitionmentioning

confidence: 99%

“…In comparison to E. coli, the inhibitor CHIR-090 elicits a substantially different cellular response in P. aeruginosa (45). Instead of LpxC or FAB enzymes, upregulated marker proteins included proteins involved in precursor supply, iron acquisition, DNA replication and export systems.…”

Section: Species-specific Responses To Lpxc Inhibitors In Gram-negati...mentioning

confidence: 99%

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Same same but different – The global response ofEscherichia colito five different LpxC inhibitors

Möller,

Vázquez-Hernández,

Kutscher

et al. 2023

Preprint

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A promising but yet clinically unexploited antibiotic target in difficult-to-treat Gram-negative bacteria is LpxC, the key enzyme in the biosynthesis of lipopolysaccharides (LPS), which are the major constituents of the outer membrane. To gain insights into the mode of action of five different LpxC inhibitors, we conducted a comparative phenotypic and proteomic analysis. All five compounds bound to purified LpxC from Escherichia coli. Treatment of E. coli with these compounds changed the cell shape and stabilized LpxC suggesting that the FtsH-mediated turnover is impaired. LpxC inhibition sensitized E. coli to the cell wall antibiotic vancomycin, which typically does not cross the outer membrane. Four of the five compounds led to an accumulation of lyso-PE, a cleavage product of phosphatidylethanolamine (PE), generated by the phospholipase PldA. The combined results suggested an imbalance in phospholipid (PL) and LPS biosynthesis, which was corroborated by the global proteome response to treatment with the LpxC inhibitors. Apart from LpxC itself, FabA and FabB responsible for the biosynthesis of unsaturated fatty acids, were consistently upregulated. Our work also shows that antibiotics targeting the same enzyme do not necessarily elicit identical cellular responses. Compound-specific marker proteins belonged to different functional categories, like stress responses, nucleotide or amino acid metabolism and quorum sensing. These findings provide new insights into common and distinct cellular defense mechanisms against LpxC inhibition. Moreover, they support a delicate balance between LPS and PL biosynthesis with great potential as point of attack for antimicrobial intervention.

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Section: Species-specific Responses To Lpxc Inhibitors In Gram-negati...supporting

confidence: 50%

“…Like many other antimicrobial compounds (44), the LpxC inhibitors seem to be exported by multi-drug efflux pumps. This was also shown to be case for CHIR-090 in P. aeruginosa (45,46).…”

Section: Similar Yet Different Responses Of E Coli To Lpxc Inhibitionmentioning

confidence: 52%

Section: Similar Yet Different Responses Of E Coli To Lpxc Inhibitionmentioning

confidence: 99%

Section: Species-specific Responses To Lpxc Inhibitors In Gram-negati...mentioning

confidence: 99%

See 2 more Smart Citations

Same same but different – The global response ofEscherichia colito five different LpxC inhibitors

Möller,

Vázquez-Hernández,

Kutscher

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Some species of bacteria respond to the presence of antibiotics by modulating their gene and protein expression levels in efforts to overcome those stresses [7][8][9][10][11][12]. For examples, increasing production of efflux pumps or altering the relative expression levels of proteins involved with cell wall synthesis.…”

Section: Introductionmentioning

confidence: 99%

Borrelia burgdorferi, the Lyme disease spirochete, possesses genetically-encoded responses to doxycycline, but not to amoxicillin

Saylor

Casselli²,

Lethbridge³

et al. 2022

PLoS ONE

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Some species of bacteria respond to antibiotic stresses by altering their transcription profiles, in order to produce proteins that provide protection against the antibiotic. Understanding these compensatory mechanisms allows for informed treatment strategies, and could lead to the development of improved therapeutics. To this end, studies were performed to determine whether Borrelia burgdorferi, the spirochetal agent of Lyme disease, also exhibits genetically-encoded responses to the commonly prescribed antibiotics doxycycline and amoxicillin. After culturing for 24 h in a sublethal concentration of doxycycline, there were significant increases in a substantial number of transcripts for proteins that are involved with translation. In contrast, incubation with a sublethal concentration of amoxicillin did not lead to significant changes in levels of any bacterial transcript. We conclude that B. burgdorferi has a mechanism(s) that detects translational inhibition by doxycycline, and increases production of mRNAs for proteins involved with translation machinery in an attempt to compensate for that stress.

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Common and varied molecular responses of Escherichia coli to five different inhibitors of the lipopolysaccharide biosynthetic enzyme LpxC

Möller,

Vázquez-Hernández,

Kutscher

et al. 2024

Journal of Biological Chemistry

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Adaptive Responses of Pseudomonas aeruginosa to Treatment with Antibiotics

Cited by 9 publications

References 72 publications

Same same but different – The global response ofEscherichia colito five different LpxC inhibitors

Same same but different – The global response ofEscherichia colito five different LpxC inhibitors

Borrelia burgdorferi, the Lyme disease spirochete, possesses genetically-encoded responses to doxycycline, but not to amoxicillin

Common and varied molecular responses of Escherichia coli to five different inhibitors of the lipopolysaccharide biosynthetic enzyme LpxC

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