title: Mechanism of sulphadiazine enhancement of trimethoprim activity against sulphadiazine-resistant Enterococcus faecalis.
abstract: Sulphadiazine had little or no antibacterial effect against three strains of Enterococcus faecalis (MICs of above 3600 mg/L) but it caused approximately six-fold increases in bacterial uptake of trimethoprim, increased release of bacterial ATP and produced ultrastructural damage to both the trimethoprim resistant E. faecalis 463 and the trimethoprim sensitive NCTC 5957. MICs of trimethoprim were 0.6, 0.8 and 76.8 mg/L for E. faecalis NCTC 775, NCTC 5957 and 463 respectively. When log phase E. faecalis 463 and NCTC 5957 were grown for 4 h in trimethoprim 56 and 0.6 mg/L plus sulphadiazine 320 and 100 mg/L respectively there was an approximate ten-fold and nine-fold increase in uptake of sulphadiazine and a two-fold increase in leakage of ATP. Trimethoprim caused more damage to the cell wall and cytoplasmic membrane than sulphadiazine but the combination of sulphadiazine plus trimethoprim caused the most cell damage. The increased activity observed with the combination seems very likely to have resulted from the increased uptakes of the antibacterials, which in turn had resulted from the cell wall damage and consequent increased cell permeability caused by each antibacterial. It is proposed that a markedly subinhibitory concentration of sulphadiazine enhanced the antibacterial activity of trimethoprim against all three strains of E. faecalis by this mechanism.
authors.affiliation: School of Pharmacy, Robert Gordon University, Aberdeen, UK.
authors.forename: R M
authors.initials: RM
authors.lastname: Richards
authors.forename: J Z
authors.initials: JZ
authors.lastname: Xing
authors.forename: D W
authors.initials: DW
authors.lastname: Gregory
authors.forename: D
authors.initials: D
authors.lastname: Marshall
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology*; D004352:Drug Resistance, Microbial; D004357:Drug Synergism; D013293:Enterococcus faecalis / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism / Q000648:ultrastructure; D008566:Membranes / Q000187:drug effects / Q000648:ultrastructure; D008826:Microbial Sensitivity Tests; D008854:Microscopy, Electron; D010539:Permeability; D013411:Sulfadiazine / Q000378:metabolism / Q000494:pharmacology*; D014295:Trimethoprim / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D013411:Sulfadiazine; D000255:Adenosine Triphosphate; D014295:Trimethoprim