Resistance trimethoprim

Accessory DHPS enzymes confer resistance to sulfonamides. Two different types encoded by the genes sull (located on transposons) and sulll (located on plasmids) have been described. These resistance determinants are often genetically linked to trimethoprim resistance genes. Therefore, the combination of sulfonamide antibiotics with trimethoprim does not prevent resistance selection. 

Figure 5.10. Protein complementation assay using murine DHFR. The F[l,2] and F[3] fragments are each fused to the homodimerizing GCN4 leucine zipper protein. A. Transformation of both Z-F[l,2] and Z-F[3] constructs results in reconstituted DHFR and growth of E. coh on agar plates containing trimethoprim. B. Transformation of Z-F[l,2] or Z-F[3] alone does not result in trimethoprim resistant E. coli cells. Figure adapted from Pelletier et al. (1998).

Resistance can develop from alterations in dihydrofolate reductase, bacterial impermeability to the drug, and by overproduction of the dihydrofolate reductase. The most important mechanism of bacterial resistance to trimethoprim clinically is the production of plasmid-encoded trimethoprim-resistant forms of dihydrofolate reductase. 

Resistance can emerge by mutation, though more commonly it is due to plasmid-encoded trimethoprim-resistant dihydrofolate reductases. These resistant enzymes may be located within transposons on conjugative plasmids that exhibit a broad host range, accounting for rapid and widespread dissemination of trimethoprim resistance among numerous bacterial species. 

Correct answer = C. Trimethoprim is 20 to 50 times more potent than sulfamethoxazole. It inhibits the enzyme dihydrofolate reductase, thus preventing both purine and pyrimidine synthesis. Trimethoprim resistance has been observed in gram-negative bacteria caused by the presence of a plasmid that codes for an altered dihydrofolate reductase with a lower affinity for the drug. 

Plasmid- and transposon-mediated resistance to trimethoprim involves a by-pass of the sensitive step by duplication of the chromosomally-encoded dihydrofolate reductase (DHFR) target enzyme [203]. Several trimethoprim-resistant bacterial DHFRs have been identified, resistance ensuing because of altered enzyme target sites [204], Low-level resistance to tetracyclines arises in E. coli as a result of chromosomal mutations leading to loss of the outer membrane porin OmpF through which these drugs normally pass [6, 193],... 

Bacteria have developed several mechanisms that make them resistant to trimethoprim. Resistance can occur rapidly, and has been reported in Europe, the USA, Asia, and South America, which may account for the fact that trimethoprim is usually used in combination (1,167,168). However, the clinical significance of resistance to trimethoprim has been debated (1,7,16,169). 

Dornbusch K, Toivanen P. Effect of trimethoprim or trimethoprim/sulphamethoxazole usage on the emergence of trimethoprim resistance in urinary tract pathogens. Scand J Infect Dis 1981 13(3) 203-10. 

Huovinen P, Toivanen P. Trimethoprim resistance in Finland after five years use of plain trimethoprim. BMJ 1980 280(6207) 72-4. 

Trimethoprim competitively inhibits dihydrofolate reductase (DHFR) and resistance can be caused by overproduction of host DHFR, mutation in the structural gene for DHFR and acquisition of the dfr gene encoding a resistant form. There are at least 15 DHFR enzyme types based on sequence homology and acquisition of dfr genes encoding alternative DHFR of type I, II or V is the most common mechanism of trimethoprim resistance among the Enterobacteriaceae. 

Despite its apparent simplicity, on the basis of an extraordinarily large amount of experimental data, the reaction catalyzed by dihydrofolate reductase has been dissected into a complex series of reaction steps. A comparison between the E. coli enzyme and an R-plasmid-coded dihydrofolate reductase involved in trimethoprim resistance indicates that the chromosomal enzyme has evolved to a virtually perfect catalytic process. ... 

M Fornasini, RR Reves, BE Murray, LK Pickering. Trimethoprim-resistant Escherichia coli in households of children attending day care centers. J Infect Dis 166(2) 326-330, 1992. 

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