Identification and validation of a novel anti-virulent that binds to pyoverdine and inhibits its function
Pseudomonas aeruginosa: causes serious infections in patients with compromised immune systems and exhibits resistance to multiple antibiotics. The rising threat of antimicrobial resistance means that new methods are necessary for treating microbial infections. We conducted a high-throughput screen f...
Ausführliche Beschreibung
Autor*in: |
Xu Wang [verfasserIn] Quinn Kleerekoper [verfasserIn] Alexey V. Revtovich [verfasserIn] Donghoon Kang [verfasserIn] Natalia V. Kirienko [verfasserIn] |
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E-Artikel |
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Sprache: |
Englisch |
Erschienen: |
2020 |
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Schlagwörter: |
pseudomonas aeruginosa (p. aeruginosa) |
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Übergeordnetes Werk: |
In: Virulence - Taylor & Francis Group, 2018, 11(2020), 1, Seite 1293-1309 |
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Übergeordnetes Werk: |
volume:11 ; year:2020 ; number:1 ; pages:1293-1309 |
Links: |
Link aufrufen |
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DOI / URN: |
10.1080/21505594.2020.1819144 |
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Katalog-ID: |
DOAJ016636988 |
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520 | |a Pseudomonas aeruginosa: causes serious infections in patients with compromised immune systems and exhibits resistance to multiple antibiotics. The rising threat of antimicrobial resistance means that new methods are necessary for treating microbial infections. We conducted a high-throughput screen for compounds that can quench the innate fluorescence of the chromophore region of the P. aeruginosa siderophore pyoverdine, a key virulence factor. Several hits were identified that effectively quench pyoverdine fluorescence, and two compounds considerably improved the survival of Caenorhabditis elegans when worms were challenged with P. aeruginosa. Commercially available analogs of the best hit, PQ3, were tested for their ability to rescue C. elegans from P. aeruginosa and to interact with pyoverdine via fluorescence and solution NMR spectroscopy. 1H-15N and 1H-13C HSQC NMR were used to identify the binding site of PQ3c. The structure model of pyoverdine in complex with PQ3c was obtained using molecular docking and molecular dynamics simulations. PQ3c occupied a shallow groove on pyoverdine formed by the chromophore and N-terminal residues of the peptide chain. Electrostatic interactions and π-orbital stacking drove stabilization of this binding. PQ3c may serve as a scaffold for the development of pyoverdine inhibitors with higher potency and specificity. The discovery of a small-molecule binding site on apo-pyoverdine with functional significance provides a new direction in the search of therapeutically effective reagent to treat P. aeruginosa infections. Abbreviations: NMR: nuclear magnetic resonance; SAR: structure–activity relationship; MD: molecular dynamics; RMSF: root-mean-square fluctuation; HSQC: heteronuclear single quantum correlation; DMSO: dimethyl sulfoxide; Δδavg: average amide chemical shift change; DSS: 2,2-dimethyl-2-silapentane-5-sulfonate; RMSD: root-mean-square deviation; LJ-SR: Lennard–Jones short-range; Coul-SR: Coulombic short-range; FRET: fluorescence resonance energy transfer | ||
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10.1080/21505594.2020.1819144 doi (DE-627)DOAJ016636988 (DE-599)DOAJ4437b111cd7e4b2d836143b11e508f2d DE-627 ger DE-627 rakwb eng RC109-216 Xu Wang verfasserin aut Identification and validation of a novel anti-virulent that binds to pyoverdine and inhibits its function 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Pseudomonas aeruginosa: causes serious infections in patients with compromised immune systems and exhibits resistance to multiple antibiotics. The rising threat of antimicrobial resistance means that new methods are necessary for treating microbial infections. We conducted a high-throughput screen for compounds that can quench the innate fluorescence of the chromophore region of the P. aeruginosa siderophore pyoverdine, a key virulence factor. Several hits were identified that effectively quench pyoverdine fluorescence, and two compounds considerably improved the survival of Caenorhabditis elegans when worms were challenged with P. aeruginosa. Commercially available analogs of the best hit, PQ3, were tested for their ability to rescue C. elegans from P. aeruginosa and to interact with pyoverdine via fluorescence and solution NMR spectroscopy. 1H-15N and 1H-13C HSQC NMR were used to identify the binding site of PQ3c. The structure model of pyoverdine in complex with PQ3c was obtained using molecular docking and molecular dynamics simulations. PQ3c occupied a shallow groove on pyoverdine formed by the chromophore and N-terminal residues of the peptide chain. Electrostatic interactions and π-orbital stacking drove stabilization of this binding. PQ3c may serve as a scaffold for the development of pyoverdine inhibitors with higher potency and specificity. The discovery of a small-molecule binding site on apo-pyoverdine with functional significance provides a new direction in the search of therapeutically effective reagent to treat P. aeruginosa infections. Abbreviations: NMR: nuclear magnetic resonance; SAR: structure–activity relationship; MD: molecular dynamics; RMSF: root-mean-square fluctuation; HSQC: heteronuclear single quantum correlation; DMSO: dimethyl sulfoxide; Δδavg: average amide chemical shift change; DSS: 2,2-dimethyl-2-silapentane-5-sulfonate; RMSD: root-mean-square deviation; LJ-SR: Lennard–Jones short-range; Coul-SR: Coulombic short-range; FRET: fluorescence resonance energy transfer pseudomonas aeruginosa (p. aeruginosa) pyoverdine solution nuclear magnetic resonance (nmr) in silico structure modeling structure-activity relationship (sar) Infectious and parasitic diseases Quinn Kleerekoper verfasserin aut Alexey V. Revtovich verfasserin aut Donghoon Kang verfasserin aut Natalia V. Kirienko verfasserin aut In Virulence Taylor & Francis Group, 2018 11(2020), 1, Seite 1293-1309 (DE-627)689717296 (DE-600)2657572-3 21505608 nnns volume:11 year:2020 number:1 pages:1293-1309 https://doi.org/10.1080/21505594.2020.1819144 kostenfrei https://doaj.org/article/4437b111cd7e4b2d836143b11e508f2d kostenfrei http://dx.doi.org/10.1080/21505594.2020.1819144 kostenfrei https://doaj.org/toc/2150-5594 Journal toc kostenfrei https://doaj.org/toc/2150-5608 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2020 1 1293-1309 |
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10.1080/21505594.2020.1819144 doi (DE-627)DOAJ016636988 (DE-599)DOAJ4437b111cd7e4b2d836143b11e508f2d DE-627 ger DE-627 rakwb eng RC109-216 Xu Wang verfasserin aut Identification and validation of a novel anti-virulent that binds to pyoverdine and inhibits its function 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Pseudomonas aeruginosa: causes serious infections in patients with compromised immune systems and exhibits resistance to multiple antibiotics. The rising threat of antimicrobial resistance means that new methods are necessary for treating microbial infections. We conducted a high-throughput screen for compounds that can quench the innate fluorescence of the chromophore region of the P. aeruginosa siderophore pyoverdine, a key virulence factor. Several hits were identified that effectively quench pyoverdine fluorescence, and two compounds considerably improved the survival of Caenorhabditis elegans when worms were challenged with P. aeruginosa. Commercially available analogs of the best hit, PQ3, were tested for their ability to rescue C. elegans from P. aeruginosa and to interact with pyoverdine via fluorescence and solution NMR spectroscopy. 1H-15N and 1H-13C HSQC NMR were used to identify the binding site of PQ3c. The structure model of pyoverdine in complex with PQ3c was obtained using molecular docking and molecular dynamics simulations. PQ3c occupied a shallow groove on pyoverdine formed by the chromophore and N-terminal residues of the peptide chain. Electrostatic interactions and π-orbital stacking drove stabilization of this binding. PQ3c may serve as a scaffold for the development of pyoverdine inhibitors with higher potency and specificity. The discovery of a small-molecule binding site on apo-pyoverdine with functional significance provides a new direction in the search of therapeutically effective reagent to treat P. aeruginosa infections. Abbreviations: NMR: nuclear magnetic resonance; SAR: structure–activity relationship; MD: molecular dynamics; RMSF: root-mean-square fluctuation; HSQC: heteronuclear single quantum correlation; DMSO: dimethyl sulfoxide; Δδavg: average amide chemical shift change; DSS: 2,2-dimethyl-2-silapentane-5-sulfonate; RMSD: root-mean-square deviation; LJ-SR: Lennard–Jones short-range; Coul-SR: Coulombic short-range; FRET: fluorescence resonance energy transfer pseudomonas aeruginosa (p. aeruginosa) pyoverdine solution nuclear magnetic resonance (nmr) in silico structure modeling structure-activity relationship (sar) Infectious and parasitic diseases Quinn Kleerekoper verfasserin aut Alexey V. Revtovich verfasserin aut Donghoon Kang verfasserin aut Natalia V. Kirienko verfasserin aut In Virulence Taylor & Francis Group, 2018 11(2020), 1, Seite 1293-1309 (DE-627)689717296 (DE-600)2657572-3 21505608 nnns volume:11 year:2020 number:1 pages:1293-1309 https://doi.org/10.1080/21505594.2020.1819144 kostenfrei https://doaj.org/article/4437b111cd7e4b2d836143b11e508f2d kostenfrei http://dx.doi.org/10.1080/21505594.2020.1819144 kostenfrei https://doaj.org/toc/2150-5594 Journal toc kostenfrei https://doaj.org/toc/2150-5608 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2020 1 1293-1309 |
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10.1080/21505594.2020.1819144 doi (DE-627)DOAJ016636988 (DE-599)DOAJ4437b111cd7e4b2d836143b11e508f2d DE-627 ger DE-627 rakwb eng RC109-216 Xu Wang verfasserin aut Identification and validation of a novel anti-virulent that binds to pyoverdine and inhibits its function 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Pseudomonas aeruginosa: causes serious infections in patients with compromised immune systems and exhibits resistance to multiple antibiotics. The rising threat of antimicrobial resistance means that new methods are necessary for treating microbial infections. We conducted a high-throughput screen for compounds that can quench the innate fluorescence of the chromophore region of the P. aeruginosa siderophore pyoverdine, a key virulence factor. Several hits were identified that effectively quench pyoverdine fluorescence, and two compounds considerably improved the survival of Caenorhabditis elegans when worms were challenged with P. aeruginosa. Commercially available analogs of the best hit, PQ3, were tested for their ability to rescue C. elegans from P. aeruginosa and to interact with pyoverdine via fluorescence and solution NMR spectroscopy. 1H-15N and 1H-13C HSQC NMR were used to identify the binding site of PQ3c. The structure model of pyoverdine in complex with PQ3c was obtained using molecular docking and molecular dynamics simulations. PQ3c occupied a shallow groove on pyoverdine formed by the chromophore and N-terminal residues of the peptide chain. Electrostatic interactions and π-orbital stacking drove stabilization of this binding. PQ3c may serve as a scaffold for the development of pyoverdine inhibitors with higher potency and specificity. The discovery of a small-molecule binding site on apo-pyoverdine with functional significance provides a new direction in the search of therapeutically effective reagent to treat P. aeruginosa infections. Abbreviations: NMR: nuclear magnetic resonance; SAR: structure–activity relationship; MD: molecular dynamics; RMSF: root-mean-square fluctuation; HSQC: heteronuclear single quantum correlation; DMSO: dimethyl sulfoxide; Δδavg: average amide chemical shift change; DSS: 2,2-dimethyl-2-silapentane-5-sulfonate; RMSD: root-mean-square deviation; LJ-SR: Lennard–Jones short-range; Coul-SR: Coulombic short-range; FRET: fluorescence resonance energy transfer pseudomonas aeruginosa (p. aeruginosa) pyoverdine solution nuclear magnetic resonance (nmr) in silico structure modeling structure-activity relationship (sar) Infectious and parasitic diseases Quinn Kleerekoper verfasserin aut Alexey V. Revtovich verfasserin aut Donghoon Kang verfasserin aut Natalia V. Kirienko verfasserin aut In Virulence Taylor & Francis Group, 2018 11(2020), 1, Seite 1293-1309 (DE-627)689717296 (DE-600)2657572-3 21505608 nnns volume:11 year:2020 number:1 pages:1293-1309 https://doi.org/10.1080/21505594.2020.1819144 kostenfrei https://doaj.org/article/4437b111cd7e4b2d836143b11e508f2d kostenfrei http://dx.doi.org/10.1080/21505594.2020.1819144 kostenfrei https://doaj.org/toc/2150-5594 Journal toc kostenfrei https://doaj.org/toc/2150-5608 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2020 1 1293-1309 |
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10.1080/21505594.2020.1819144 doi (DE-627)DOAJ016636988 (DE-599)DOAJ4437b111cd7e4b2d836143b11e508f2d DE-627 ger DE-627 rakwb eng RC109-216 Xu Wang verfasserin aut Identification and validation of a novel anti-virulent that binds to pyoverdine and inhibits its function 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Pseudomonas aeruginosa: causes serious infections in patients with compromised immune systems and exhibits resistance to multiple antibiotics. The rising threat of antimicrobial resistance means that new methods are necessary for treating microbial infections. We conducted a high-throughput screen for compounds that can quench the innate fluorescence of the chromophore region of the P. aeruginosa siderophore pyoverdine, a key virulence factor. Several hits were identified that effectively quench pyoverdine fluorescence, and two compounds considerably improved the survival of Caenorhabditis elegans when worms were challenged with P. aeruginosa. Commercially available analogs of the best hit, PQ3, were tested for their ability to rescue C. elegans from P. aeruginosa and to interact with pyoverdine via fluorescence and solution NMR spectroscopy. 1H-15N and 1H-13C HSQC NMR were used to identify the binding site of PQ3c. The structure model of pyoverdine in complex with PQ3c was obtained using molecular docking and molecular dynamics simulations. PQ3c occupied a shallow groove on pyoverdine formed by the chromophore and N-terminal residues of the peptide chain. Electrostatic interactions and π-orbital stacking drove stabilization of this binding. PQ3c may serve as a scaffold for the development of pyoverdine inhibitors with higher potency and specificity. The discovery of a small-molecule binding site on apo-pyoverdine with functional significance provides a new direction in the search of therapeutically effective reagent to treat P. aeruginosa infections. Abbreviations: NMR: nuclear magnetic resonance; SAR: structure–activity relationship; MD: molecular dynamics; RMSF: root-mean-square fluctuation; HSQC: heteronuclear single quantum correlation; DMSO: dimethyl sulfoxide; Δδavg: average amide chemical shift change; DSS: 2,2-dimethyl-2-silapentane-5-sulfonate; RMSD: root-mean-square deviation; LJ-SR: Lennard–Jones short-range; Coul-SR: Coulombic short-range; FRET: fluorescence resonance energy transfer pseudomonas aeruginosa (p. aeruginosa) pyoverdine solution nuclear magnetic resonance (nmr) in silico structure modeling structure-activity relationship (sar) Infectious and parasitic diseases Quinn Kleerekoper verfasserin aut Alexey V. Revtovich verfasserin aut Donghoon Kang verfasserin aut Natalia V. Kirienko verfasserin aut In Virulence Taylor & Francis Group, 2018 11(2020), 1, Seite 1293-1309 (DE-627)689717296 (DE-600)2657572-3 21505608 nnns volume:11 year:2020 number:1 pages:1293-1309 https://doi.org/10.1080/21505594.2020.1819144 kostenfrei https://doaj.org/article/4437b111cd7e4b2d836143b11e508f2d kostenfrei http://dx.doi.org/10.1080/21505594.2020.1819144 kostenfrei https://doaj.org/toc/2150-5594 Journal toc kostenfrei https://doaj.org/toc/2150-5608 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2020 1 1293-1309 |
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Identification and validation of a novel anti-virulent that binds to pyoverdine and inhibits its function |
abstract |
Pseudomonas aeruginosa: causes serious infections in patients with compromised immune systems and exhibits resistance to multiple antibiotics. The rising threat of antimicrobial resistance means that new methods are necessary for treating microbial infections. We conducted a high-throughput screen for compounds that can quench the innate fluorescence of the chromophore region of the P. aeruginosa siderophore pyoverdine, a key virulence factor. Several hits were identified that effectively quench pyoverdine fluorescence, and two compounds considerably improved the survival of Caenorhabditis elegans when worms were challenged with P. aeruginosa. Commercially available analogs of the best hit, PQ3, were tested for their ability to rescue C. elegans from P. aeruginosa and to interact with pyoverdine via fluorescence and solution NMR spectroscopy. 1H-15N and 1H-13C HSQC NMR were used to identify the binding site of PQ3c. The structure model of pyoverdine in complex with PQ3c was obtained using molecular docking and molecular dynamics simulations. PQ3c occupied a shallow groove on pyoverdine formed by the chromophore and N-terminal residues of the peptide chain. Electrostatic interactions and π-orbital stacking drove stabilization of this binding. PQ3c may serve as a scaffold for the development of pyoverdine inhibitors with higher potency and specificity. The discovery of a small-molecule binding site on apo-pyoverdine with functional significance provides a new direction in the search of therapeutically effective reagent to treat P. aeruginosa infections. Abbreviations: NMR: nuclear magnetic resonance; SAR: structure–activity relationship; MD: molecular dynamics; RMSF: root-mean-square fluctuation; HSQC: heteronuclear single quantum correlation; DMSO: dimethyl sulfoxide; Δδavg: average amide chemical shift change; DSS: 2,2-dimethyl-2-silapentane-5-sulfonate; RMSD: root-mean-square deviation; LJ-SR: Lennard–Jones short-range; Coul-SR: Coulombic short-range; FRET: fluorescence resonance energy transfer |
abstractGer |
Pseudomonas aeruginosa: causes serious infections in patients with compromised immune systems and exhibits resistance to multiple antibiotics. The rising threat of antimicrobial resistance means that new methods are necessary for treating microbial infections. We conducted a high-throughput screen for compounds that can quench the innate fluorescence of the chromophore region of the P. aeruginosa siderophore pyoverdine, a key virulence factor. Several hits were identified that effectively quench pyoverdine fluorescence, and two compounds considerably improved the survival of Caenorhabditis elegans when worms were challenged with P. aeruginosa. Commercially available analogs of the best hit, PQ3, were tested for their ability to rescue C. elegans from P. aeruginosa and to interact with pyoverdine via fluorescence and solution NMR spectroscopy. 1H-15N and 1H-13C HSQC NMR were used to identify the binding site of PQ3c. The structure model of pyoverdine in complex with PQ3c was obtained using molecular docking and molecular dynamics simulations. PQ3c occupied a shallow groove on pyoverdine formed by the chromophore and N-terminal residues of the peptide chain. Electrostatic interactions and π-orbital stacking drove stabilization of this binding. PQ3c may serve as a scaffold for the development of pyoverdine inhibitors with higher potency and specificity. The discovery of a small-molecule binding site on apo-pyoverdine with functional significance provides a new direction in the search of therapeutically effective reagent to treat P. aeruginosa infections. Abbreviations: NMR: nuclear magnetic resonance; SAR: structure–activity relationship; MD: molecular dynamics; RMSF: root-mean-square fluctuation; HSQC: heteronuclear single quantum correlation; DMSO: dimethyl sulfoxide; Δδavg: average amide chemical shift change; DSS: 2,2-dimethyl-2-silapentane-5-sulfonate; RMSD: root-mean-square deviation; LJ-SR: Lennard–Jones short-range; Coul-SR: Coulombic short-range; FRET: fluorescence resonance energy transfer |
abstract_unstemmed |
Pseudomonas aeruginosa: causes serious infections in patients with compromised immune systems and exhibits resistance to multiple antibiotics. The rising threat of antimicrobial resistance means that new methods are necessary for treating microbial infections. We conducted a high-throughput screen for compounds that can quench the innate fluorescence of the chromophore region of the P. aeruginosa siderophore pyoverdine, a key virulence factor. Several hits were identified that effectively quench pyoverdine fluorescence, and two compounds considerably improved the survival of Caenorhabditis elegans when worms were challenged with P. aeruginosa. Commercially available analogs of the best hit, PQ3, were tested for their ability to rescue C. elegans from P. aeruginosa and to interact with pyoverdine via fluorescence and solution NMR spectroscopy. 1H-15N and 1H-13C HSQC NMR were used to identify the binding site of PQ3c. The structure model of pyoverdine in complex with PQ3c was obtained using molecular docking and molecular dynamics simulations. PQ3c occupied a shallow groove on pyoverdine formed by the chromophore and N-terminal residues of the peptide chain. Electrostatic interactions and π-orbital stacking drove stabilization of this binding. PQ3c may serve as a scaffold for the development of pyoverdine inhibitors with higher potency and specificity. The discovery of a small-molecule binding site on apo-pyoverdine with functional significance provides a new direction in the search of therapeutically effective reagent to treat P. aeruginosa infections. Abbreviations: NMR: nuclear magnetic resonance; SAR: structure–activity relationship; MD: molecular dynamics; RMSF: root-mean-square fluctuation; HSQC: heteronuclear single quantum correlation; DMSO: dimethyl sulfoxide; Δδavg: average amide chemical shift change; DSS: 2,2-dimethyl-2-silapentane-5-sulfonate; RMSD: root-mean-square deviation; LJ-SR: Lennard–Jones short-range; Coul-SR: Coulombic short-range; FRET: fluorescence resonance energy transfer |
collection_details |
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container_issue |
1 |
title_short |
Identification and validation of a novel anti-virulent that binds to pyoverdine and inhibits its function |
url |
https://doi.org/10.1080/21505594.2020.1819144 https://doaj.org/article/4437b111cd7e4b2d836143b11e508f2d http://dx.doi.org/10.1080/21505594.2020.1819144 https://doaj.org/toc/2150-5594 https://doaj.org/toc/2150-5608 |
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author2 |
Quinn Kleerekoper Alexey V. Revtovich Donghoon Kang Natalia V. Kirienko |
author2Str |
Quinn Kleerekoper Alexey V. Revtovich Donghoon Kang Natalia V. Kirienko |
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doi_str |
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callnumber-a |
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up_date |
2024-07-03T22:11:15.891Z |
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