Small molecule G-quadruplex ligands are antibacterial candidates for Gram-negative bacteria
ABSTRACT There is great need for novel strategies to tackle antimicrobial resistance, in particular in Gram-negative species such asEscherichia colithat cause opportunistic infections of already compromised patients. Here we demonstrate, following a screen of G-quadruplex (G4) ligand candidates, that a novel pyridinium-functionalized azobenzeneL9shows promising antibacterial activity (MIC values ≤ 4 μg/mL) against multi-drug resistantE. coli. Tandem Mass Tag (TMT) proteomics ofE. colitreated with sub-lethal concentrations ofL9, identified that, consistent with its superior antibacterial activity,L9treatment influences expression levels of more G4-associated proteins than the analogous ligandsL5(stiff-stilbene) or pyridostatin (PDS), and upregulates multiple essential proteins involved in translation. Biophysical analysis showedL9binds potential target G4-containing sequences, identified from proteomic experiments and by bioinformatics, with variable affinity, in contrast to the two comparator G4 ligands (L5, PDS) that better stabilize G4 structures but have lower antimicrobial activity. Fluorescence microscopy-based Bacterial Cytological Profiling (BCP) suggests that theL9mechanism of action is distinct from other antibiotic classes. These findings support strategies discovering potential G4 ligands as antibacterial candidates for priority targets such as multi-drug resistantE. coli, warranting their further exploration as potential novel therapeutic leads with G4-mediated modes of action.Abstract Figure <jats:fig id="ufig1" position="float" fig-type="figure" orientation="portrait"><jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="506212v2_ufig1" position="float" orientation="portrait" /></jats:fig>.
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Preprint| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
bioRxiv.org - (2024) vom: 10. Feb. Zur Gesamtaufnahme - year:2024 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Takebayashi, Yuiko [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2022.09.01.506212 |
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| PPN (Katalog-ID): |
XBI037180231 |
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| 100 | 1 | |a Takebayashi, Yuiko |e verfasserin |0 (orcid)0000-0002-6224-0224 |4 aut | |
| 245 | 1 | 0 | |a Small molecule G-quadruplex ligands are antibacterial candidates for Gram-negative bacteria |
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| 520 | |a ABSTRACT There is great need for novel strategies to tackle antimicrobial resistance, in particular in Gram-negative species such asEscherichia colithat cause opportunistic infections of already compromised patients. Here we demonstrate, following a screen of G-quadruplex (G4) ligand candidates, that a novel pyridinium-functionalized azobenzeneL9shows promising antibacterial activity (MIC values ≤ 4 μg/mL) against multi-drug resistantE. coli. Tandem Mass Tag (TMT) proteomics ofE. colitreated with sub-lethal concentrations ofL9, identified that, consistent with its superior antibacterial activity,L9treatment influences expression levels of more G4-associated proteins than the analogous ligandsL5(stiff-stilbene) or pyridostatin (PDS), and upregulates multiple essential proteins involved in translation. Biophysical analysis showedL9binds potential target G4-containing sequences, identified from proteomic experiments and by bioinformatics, with variable affinity, in contrast to the two comparator G4 ligands (L5, PDS) that better stabilize G4 structures but have lower antimicrobial activity. Fluorescence microscopy-based Bacterial Cytological Profiling (BCP) suggests that theL9mechanism of action is distinct from other antibiotic classes. These findings support strategies discovering potential G4 ligands as antibacterial candidates for priority targets such as multi-drug resistantE. coli, warranting their further exploration as potential novel therapeutic leads with G4-mediated modes of action.Abstract Figure <jats:fig id="ufig1" position="float" fig-type="figure" orientation="portrait"><jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="506212v2_ufig1" position="float" orientation="portrait" /></jats:fig> | ||
| 650 | 4 | |a Biology |7 (dpeaa)DE-84 | |
| 650 | 4 | |a 570 |7 (dpeaa)DE-84 | |
| 700 | 1 | |a Ramos-Soriano, Javier |0 (orcid)0000-0002-3054-0679 |4 aut | |
| 700 | 1 | |a Jiang, Y. Jennifer |4 aut | |
| 700 | 1 | |a Samphire, Jennifer |4 aut | |
| 700 | 1 | |a Belmonte-Reche, Efres |4 aut | |
| 700 | 1 | |a O’Hagan, Michael P. |0 (orcid)0000-0003-4180-3144 |4 aut | |
| 700 | 1 | |a Gurr, Catherine |4 aut | |
| 700 | 1 | |a Heesom, Kate J. |4 aut | |
| 700 | 1 | |a Lewis, Philip A. |4 aut | |
| 700 | 1 | |a Samernate, Thanadon |4 aut | |
| 700 | 1 | |a Nonejuie, Poochit |4 aut | |
| 700 | 1 | |a Spencer, James |4 aut | |
| 700 | 1 | |a Galan, M. Carmen |0 (orcid)0000-0001-7307-2871 |4 aut | |
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