title: Large scale molecular dynamics simulation of native and mutant dihydropteroate synthase-sulphanilamide complexes suggests the molecular basis for dihydropteroate synthase drug resistance.
abstract: Antibiotic resistance is hampering the efficacy of drugs in the treatment of several pathological infections. Dihydropteroate synthase (DHPS) has been targeted by sulphonamide inhibitors for the past 60 years and has developed different amino acid mutations to survive sulpha drug action. We couple homology modelling techniques and massively parallel molecular dynamics simulations to study both the drug-bound and apo forms of native and mutant DHPS. Simulations of the complex between sulphanilamide and Streptomyces pneumoniae, DHPS shows how sulphanilamide is able to position itself close to 6-hydroxymethyl-7, 8-dihydropteridine-phosphate in a suitable position for the enzymatic transformation whereas in the mutant complex the sulpha drug is expelled from the catalytic site. Our simulations, therefore, provide insight into the molecular basis for drug resistance with S. pneumoniae DHPS.
authors.affiliation: Centre for Computational Science, Department of Chemistry, University College London, Christopher Ingold Laboratories, UK.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Giordanetto
authors.forename: Philip W
authors.initials: PW
authors.lastname: Fowler
authors.forename: Mansoor
authors.initials: M
authors.lastname: Saqi
authors.forename: Peter V
authors.initials: PV
authors.lastname: Coveney
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D002384:Catalysis; D003198:Computer Simulation; D004094:Dihydropteroate Synthase / Q000737:chemistry* / Q000378:metabolism; D024881:Drug Resistance, Bacterial; D004789:Enzyme Activation; D008954:Models, Biological; D008956:Models, Chemical; D008958:Models, Molecular; D009038:Motion; D011485:Protein Binding; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D013302:Streptomyces / Q000201:enzymology*; D013329:Structure-Activity Relationship; D013424:Sulfanilamides / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D013424:Sulfanilamides; D004094:Dihydropteroate Synthase