Structural and Kinetics Studies of the Enzyme Dihydropteroate Synthase and the Implications for Antibiotic Resistance

  title={Structural and Kinetics Studies of the Enzyme Dihydropteroate Synthase and the Implications for Antibiotic Resistance},
  author={Katherine A. Ayers},
1 Citations
Substituted N-(Pyrazin-2-yl)benzenesulfonamides; Synthesis, Anti-Infective Evaluation, Cytotoxicity, and In Silico Studies
We prepared a series of substituted N-(pyrazin-2-yl)benzenesulfonamides as an attempt to investigate the effect of different linkers connecting pyrazine to benzene cores on antimicrobial activity


Dihydropteroate synthase from Streptococcus pneumoniae: structure, ligand recognition and mechanism of sulfonamide resistance.
The results show that binding of DHPPP and pABA are separate distinguishable events in the reaction cycle, and that mutations which confer resistance to sulfonamide drugs act exclusively on the second step in the binding process.
Dihydropteroate Synthetase From Bacillus anthracis
Crystal structure of Mycobacterium tuberculosis 7,8-dihydropteroate synthase in complex with pterin monophosphate: new insight into the enzymatic mechanism and sulfa-drug action.
The Mtb DHPS structure hints at a mechanism in which both loops 1 and 2 play important roles in catalysis by shielding the active site from bulk solvent and allowing pyrophosphoryl transfer to occur and a highly conserved pterin binding pocket that may be exploited for the design of novel antimycobacterial agents.
Sulfonamide resistance: mechanisms and trends.
  • O. Sköld
  • Biology, Medicine
    Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy
  • 2000
Remarkably, the corresponding DHPS enzymes show pronounced insensitivity to sulfonamides but normal binding to the p -aminobenzoic acid substrate, despite the close structural similarity between substrate and inhibitor.
Cloning and Expression of Mycobacterium tuberculosis and Mycobacterium leprae Dihydropteroate Synthase in Escherichia coli
Steady-state kinetic parameters for dihydropteroate synthases from both M. tuberculosis and M. leprae were determined, and the antimycobacterial agent p-aminosalicylate, a putative dihydrocarbon synthase inhibitor, was a poor inhibitor of the enzymes.
[Biosynthesis of folic acid].
Phaser crystallographic software
A description is given of Phaser-2.1: software for phasing macromolecular crystal structures by molecular replacement and single-wavelength anomalous dispersion phasing.
Resistance to trimethoprim and sulfonamides.
  • O. Sköld
  • Biology, Medicine
    Veterinary research
  • 2001
The trade-off, seen in laboratory experiments selecting resistance mutants, seems to be adjusted for by compensatory mutations in clinically isolated drug-resistant pathogens, which means that susceptibility will not return after suspending the use of sulfonamide and trimethoprim.
Crystal structure of the anti-bacterial sulfonamide drug target dihydropteroate synthase
The crystal structure of E.coli DHPS at 2.0 Å resolution refined to an R-factor of 0.185 is reported, finding the 7,8-dihydropterin pyrophosphate substrate binds in a deep cleft in the barrel, whilst sulfanilamide binds closer to the surface.
Reductive alkylation of lysine residues to alter crystallization properties of proteins.