Dihydrofolate reductase
Bacteria

Trimethoprim interrupts folate metabolism by inhibition of the activity of dihydrofolase reductase (DHFR), which reduces dihydrofolate to tetrahydrofolate (THF).
Trimethoprim causes protein aggregation and induction of main heat shock proteins (Hsps) in E. coli cells, which indicates that Trimethoprim presence leads to protein misfolding. Trimethoprim causes induction of DnaK, DnaJ, GroEL, ClpB, and IbpA/B Hsps. Among these Hsps, IbpA/B are most efficiently induced by Trimethoprim and coaggregates with the insoluble proteins. Upon folate stress, deletion of the delta ibpA/B operon resulted in increased protein aggregation but does not influence cell viability.

In intraperitoneal infections in mice, the CD ₅₀ values for Trimethoprim alone against H. influenzae , S. pneumoniae , E. coli and N. meningitidis , is 150 mg/kg, 335 mg/kg, 27.5 mg/kg and 8.4 mg/kg, respectively.