Water-mediated network in the resistance mechanism of fosfomycin

James McClory, Jun Tang Lin, David J. Timson, Jian Zhang, Meilan Huang

Research output: Contribution to journalArticle

Abstract

Fosfomycin Resistance Kinase A (FomA) catalyzes the phosphorylation of fosfomycin, which is an effective antibiotic for treating urinary tract infections. Understanding the chemical reaction mechanism is essential for developing strategies to counter the resistance of fosfomycin in clinical settings. Here the catalytic mechanism of FomA was investigated using molecular dynamic simulations in conjunction with quantum mechanics/molecular mechanics calculations (B97d/AMBER99). Our QM/MM study disclosed that the phosphorylation reaction catalyzed by FomA follows a dissociative mechanism, in contrast to the previously proposed associative mechanism. In addition, we found that His58, a characteristic residue in the AAK family, plays a key role in positioning the phosphate group of fosfomycin in the transition state. Molecular dynamic simulations revealed the important roles of Lys9 and Lys18 in arranging the nucleotide for phosphate transfer. Furthermore, we identified a four-membered water network mediated by Asp171 and Ser13 that is critical in ordering ATP for phosphate transfer. The active structure and reaction mechanism of FomA will provide valuable insights for developing new strategies to tackle the resistance to Fosfomycin-based antibiotic therapies.

Original languageEnglish
Pages (from-to)21660-21667
Number of pages8
JournalPhysical Chemistry Chemical Physics
Volume20
Issue number33
DOIs
Publication statusPublished - 2 Aug 2018

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Fosfomycin
Water
phosphates
phosphorylation
Phosphorylation
water
antibiotics
Phosphates
Molecular dynamics
molecular dynamics
Anti-Bacterial Agents
Molecular mechanics
adenosine triphosphate
Quantum theory
nucleotides
Computer simulation
infectious diseases
positioning
quantum mechanics
Chemical reactions

Cite this

McClory, James ; Lin, Jun Tang ; Timson, David J. ; Zhang, Jian ; Huang, Meilan. / Water-mediated network in the resistance mechanism of fosfomycin. In: Physical Chemistry Chemical Physics. 2018 ; Vol. 20, No. 33. pp. 21660-21667.
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Water-mediated network in the resistance mechanism of fosfomycin. / McClory, James; Lin, Jun Tang; Timson, David J.; Zhang, Jian; Huang, Meilan.

In: Physical Chemistry Chemical Physics, Vol. 20, No. 33, 02.08.2018, p. 21660-21667.

Research output: Contribution to journalArticle

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