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...
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2020
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oai:doaj.org-article:4437b111cd7e4b2d836143b11e508f2d2021-11-17T14:21:59ZIdentification and validation of a novel anti-virulent that binds to pyoverdine and inhibits its function2150-55942150-560810.1080/21505594.2020.1819144https://doaj.org/article/4437b111cd7e4b2d836143b11e508f2d2020-12-01T00:00:00Zhttp://dx.doi.org/10.1080/21505594.2020.1819144https://doaj.org/toc/2150-5594https://doaj.org/toc/2150-5608Pseudomonas 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 transferXu WangQuinn KleerekoperAlexey V. RevtovichDonghoon KangNatalia V. KirienkoTaylor & Francis Grouparticlepseudomonas aeruginosa (p. aeruginosa)pyoverdinesolution nuclear magnetic resonance (nmr)in silico structure modelingstructure-activity relationship (sar)Infectious and parasitic diseasesRC109-216ENVirulence, Vol 11, Iss 1, Pp 1293-1309 (2020) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
pseudomonas aeruginosa (p. aeruginosa) pyoverdine solution nuclear magnetic resonance (nmr) in silico structure modeling structure-activity relationship (sar) Infectious and parasitic diseases RC109-216 |
| spellingShingle |
pseudomonas aeruginosa (p. aeruginosa) pyoverdine solution nuclear magnetic resonance (nmr) in silico structure modeling structure-activity relationship (sar) Infectious and parasitic diseases RC109-216 Xu Wang Quinn Kleerekoper Alexey V. Revtovich Donghoon Kang Natalia V. Kirienko Identification and validation of a novel anti-virulent that binds to pyoverdine and inhibits its function |
| description |
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 |
| format |
article |
| author |
Xu Wang Quinn Kleerekoper Alexey V. Revtovich Donghoon Kang Natalia V. Kirienko |
| author_facet |
Xu Wang Quinn Kleerekoper Alexey V. Revtovich Donghoon Kang Natalia V. Kirienko |
| author_sort |
Xu Wang |
| title |
Identification and validation of a novel anti-virulent that binds to pyoverdine and inhibits its function |
| title_short |
Identification and validation of a novel anti-virulent that binds to pyoverdine and inhibits its function |
| title_full |
Identification and validation of a novel anti-virulent that binds to pyoverdine and inhibits its function |
| title_fullStr |
Identification and validation of a novel anti-virulent that binds to pyoverdine and inhibits its function |
| title_full_unstemmed |
Identification and validation of a novel anti-virulent that binds to pyoverdine and inhibits its function |
| title_sort |
identification and validation of a novel anti-virulent that binds to pyoverdine and inhibits its function |
| publisher |
Taylor & Francis Group |
| publishDate |
2020 |
| url |
https://doaj.org/article/4437b111cd7e4b2d836143b11e508f2d |
| work_keys_str_mv |
AT xuwang identificationandvalidationofanovelantivirulentthatbindstopyoverdineandinhibitsitsfunction AT quinnkleerekoper identificationandvalidationofanovelantivirulentthatbindstopyoverdineandinhibitsitsfunction AT alexeyvrevtovich identificationandvalidationofanovelantivirulentthatbindstopyoverdineandinhibitsitsfunction AT donghoonkang identificationandvalidationofanovelantivirulentthatbindstopyoverdineandinhibitsitsfunction AT nataliavkirienko identificationandvalidationofanovelantivirulentthatbindstopyoverdineandinhibitsitsfunction |
| _version_ |
1718425410617737216 |