A conservative amino acid mutation in the chromosome-encoded dihydrofolate reductase confers trimethoprim resistance in Streptococcus pneumoniae

J Infect Dis. 1998 Sep;178(3):700-6. doi: 10.1086/515371.


Multidrug-resistant Streptococcus pneumoniae strains have emerged over the past decade at an alarming rate. The molecular mechanism of trimethoprim resistance was investigated in 5 pneumococcal strains isolated in the Washington, DC, area from patients with invasive infections. Cloning and sequencing of the trimethoprim resistance determinant from these pneumococci indicated that an altered chromosome-encoded dihydrofolate reductase (DHFR) was responsible for the observed resistance. Comparison of DHFR sequences from pneumococcal strains with various susceptibilities to trimethoprim, together with site-directed mutagenesis, revealed that substitution of isoleucine-100 with a leucine residue resulted in trimethoprim resistance. Hydrogen bonding between the carbonyl oxygen of isoleucine-100 and the 4-amino group of trimethoprim is proposed to play a critical role in the inhibition of DHFR by trimethoprim. This enzyme-substrate model should facilitate the design of new antibacterial agents with improved activity against S. pneumoniae.

MeSH terms

  • Amino Acid Sequence
  • Anti-Bacterial Agents / pharmacology*
  • Base Sequence
  • Chromosomes, Bacterial
  • Conserved Sequence*
  • DNA, Bacterial
  • Drug Resistance, Microbial / genetics
  • Humans
  • Molecular Sequence Data
  • Mutation*
  • Sequence Homology, Amino Acid
  • Streptococcus pneumoniae / drug effects*
  • Streptococcus pneumoniae / enzymology
  • Streptococcus pneumoniae / genetics
  • Streptococcus pneumoniae / isolation & purification
  • Tetrahydrofolate Dehydrogenase / genetics*
  • Trimethoprim / pharmacology*


  • Anti-Bacterial Agents
  • DNA, Bacterial
  • Trimethoprim
  • Tetrahydrofolate Dehydrogenase

Associated data

  • GENBANK/AF055720
  • GENBANK/AF055721
  • GENBANK/AF055722
  • GENBANK/AF055723
  • GENBANK/AF055724
  • GENBANK/AF055725
  • GENBANK/AF055726
  • GENBANK/AF055727