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Updated: Feb 6, 2026

VIGS-Mediated Forward Genetics Screening for Identification of Genes Involved in Nonhost Resistance
Published on: August 23, 2013
Water-mediated network in the resistance mechanism of fosfomycin
James McClory1, Jun-Tang Lin, David J Timson
1School of Chemistry and Chemical Engineering, Queen's University Belfast, David Keir Building, Stranmillis Road, Belfast, BT9 5AG, Northern Ireland, UK. m.huang@qub.ac.uk.
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.
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