Factors That Cause Trimethoprim Resistance in Streptococcus pyogenes

Abstract

bThe use of trimethoprim in treatment of Streptococcus pyogenes infections has long been discouraged because it has been widely believed that this pathogen is resistant to this antibiotic. To gain more insight into the extent and molecular basis of trimethoprim resistance in S. pyogenes, we tested isolates from India and Germany and sought the factors that conferred the resistance. Resistant isolates were identified in tests for trimethoprim or trimethoprim-sulfamethoxazole (SXT) susceptibility. Resistant isolates were screened for the known horizontally transferable trimethoprim-insensitive dihydrofolate reductase (dfr) genes dfrG, dfrF, dfrA, dfrD, and dfrK. The nucleotide sequence of the intrinsic dfr gene was determined for resistant isolates lacking the horizontally transferable genes. Based on tentative criteria, 69 out of 268 isolates (25.7%) from India were resistant to trimethoprim. Occurring in 42 of the 69 resistant isolates (60.9%), dfrF appeared more frequently than dfrG (23 isolates; 33.3%) in India. The dfrF gene was also present in a collection of SXT-resistant isolates from Germany, in which it was the only detected trimethoprim resistance factor. The dfrF gene caused resistance in 4 out of 5 trimethoprim-resistant isolates from the German collection. An amino acid substitution in the intrinsic dihydrofolate reductase known from trimethoprim-resistant Streptococcus pneumoniae conferred resistance to S. pyogenes isolates of emm type 102.2, which lacked other aforementioned dfr genes. Trimethoprim may be more useful in treatment of S. pyogenes infections than previously thought. However, the factors described herein may lead to the rapid development and spread of resistance of S. pyogenes to this antibiotic agent.

MRSA Isolates from United States Hospitals Carry dfrG and dfrK Resistance Genes and Succumb to Propargyl-Linked Antifolates

“…Genomic analysis revealed the presence of a second DHFR enzyme encoded by the gene, dfrG that had been integrated into the chromosome. Although this gene has been observed in S. aureus in Asia (Sekiguchi et al, 2005), Africa and European travelers (Nurjadi et al, 2014) and in Streptococcus pyogenes in India (Bergmann et al, 2014), to our knowledge, this is the first report of dfrG in North America. We then used PCR to evaluate the remaining strains for the presence of dfrG as well as two other plasmid-encoded genes, dfrA and dfrK , known to occur in S. aureus .…”

Diversity and Evolution of the Tn 5801-tet (M)-Like Integrative and Conjugative Elements among Enterococcus, Streptococcus, and Staphylococcus

“…Such an element confers resistance to trimethoprim, and it was also detected within orf14 of Tn5801 types A11 and A12 (see below), in the Tn916-like transposon (Tn6198) of Listeria monocytogenes, in the plasmid pMG1 from E. faecium, and also in Streptococcus pyogenes isolates from India (35)(36)(37). The backbone of A4 was identical to that of Tn5801 types A5 and A6, which also showed additional insertion sequences (IS) interrupting the uvrD (orf3) gene (IS30 or IS256, respectively).…”

Trimethoprim and other nonclassical antifolates an excellent template for searching modifications of dihydrofolate reductase enzyme inhibitors

“…In strains of TMP-resistant Haemophilus influenzae, changes in both promoter and coding regions of the dhfr genes have been found [64]. In case of Gram-positive bacteria it has been detected several horizontally transmissible dfrgenes, e.g., dfrG have been identified in one of the emm1-2.2 clinical isolates Streptococcus pyogenes [65,66]. Moreover DHFR encoded by dfrA was found in S. aureus, Staphylococcus epidermidis, Staphylococcus hominis, and Staphylococcus haemolyticus [67][68][69].…”