Identification and validation of a novel anti-virulent that binds to pyoverdine and inhibits its function.
Identification and validation of a novel anti-virulent that binds to pyoverdine and inhibits its function.
复制标题
鉴定和验证一种新型的与吡啶结合并抑制其功能的抗病毒药物。
DOI：
10.1080/21505594.2020.1819144
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发表时间：
2020-12
期刊：
影响因子：
5.2
通讯作者：
Kirienko NV
中科院分区：
文献类型：
--
作者：
Wang X;Kleerekoper Q;Revtovich AV;Kang D;Kirienko NV
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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影响因子：
5.5
作者：
Hess, Berk;Kutzner, Carsten;Lindahl, Erik
通讯作者：
Lindahl, Erik
影响因子：
4.8
作者：
Kirienko DR;Revtovich AV;Kirienko NV
通讯作者：
Kirienko NV
影响因子：
4.8
作者：
Kleerekoper, Quinn K.;Putkey, John A.
通讯作者：
Putkey, John A.
DOI：
10.1073/pnas.1222706110
发表时间：
2013-04-30
影响因子：
11.1
作者：
Imperi, Francesco;Massai, Francesco;Visca, Paolo
通讯作者：
Visca, Paolo
影响因子：
5.3
作者：
Burrows, Lori L.
通讯作者：
Burrows, Lori L.