Mutations of Pneumocystis jirovecii Dihydrofolate Reductase Associated with Failure of Prophylaxis

Abstract

Most drugs used for prevention and treatment of Pneumocystis jirovecii pneumonia target enzymes involved in the biosynthesis of folic acid, i.e., dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR). Emergence of P. jirovecii drug resistance has been suggested by the association between failure of prophylaxis with sulfa drugs and mutations in DHPS. However, data on the occurrence of mutations in DHFR, the target of trimethoprim and pyrimethamine, are scarce. We examined polymorphisms in P. jirovecii DHFR from 33 patients diagnosed with P. jirovecii pneumonia who were receiving prophylaxis with a DHFR inhibitor (n ‫؍‬ 15), prophylaxis without a DHFR inhibitor (n ‫؍‬ 11), or no prophylaxis (n ‫؍‬ 7). Compared to the wild-type sequence present in GenBank, 19 DHFR nucleotide substitution sites were found in 18 patients with 3 synonymous and 16 nonsynonymous mutations. Of 16 amino acid changes, 6 were located in positions conserved among distant organisms, and five of these six positions are probably involved in the putative active sites of the enzyme. Patients with failure of prophylaxis, including a DHFR inhibitor, were more likely to harbor nonsynonymous DHFR mutations than those who did not receive such prophylaxis (9 of 15 patients versus 2 of 18; P ‫؍‬ 0.008). Analysis of the rate of nonsynonymous versus synonymous mutations was consistent with selection of amino acid substitutions in patients with failure of prophylaxis including a DHFR inhibitor. The results suggest that P. jirovecii populations may evolve under selective pressure from DHFR inhibitors, in particular pyrimethamine, and that DHFR mutations may contribute to P. jirovecii drug resistance.

Pulmonary Manifestations of HIV Disease

“…Although aeroslolized pentamidine and cotrimoxazole may have equal efficacy 71 , the preferred drug is cotrimoxazole 72 but if this cannot be tolerated aerosolized pentamidine or atovaquone which have been found to have similar efficacy may be used 73 . Mutation in the dihdrofolate reductase gene may however, lead to prophylaxis failures 74,75 . An alternative drug is dapsone which appears to have an efficacy equal to that of atovaquone but which may be less safe 76 .…”

Pneumocystis jirovecii Pneumonia in AIDS Patients

“…Such mutations confer resistance to sulfa drugs in other organisms, including Escherichia coli, Streptococcus pneumoniae and Plasmodium falciparum. The P. jirovecii D H P S m u t a n t f o r m h a s a l s o b e e n s h o w n t o b e m o r e r e s i s t a n t t o sulfamethoxazole in a Saccharomyces cerevisiae model (Iliades et al, 2004), but it is still uncertain if Pneumocystis DHPS mutations lead to drug resistance in patients (Huang et al, 2000Nahimana et al, 2004). Such mutations were shown to be associated with the use of TMP-SMX or dapsone (two DHPS inhibitors), the duration of sulfa or dapsone prophylaxis and with geographic areas in which sulfamethoxazole or dapsone were commonly used for PcP prophylaxis Kazanjian et al, 2000).…”

Study of reactivity of cyanoacetohydrazonoethyl-N-ethyl-N-methyl benzenesulfonamide: preparation of novel anticancer and antimicrobial active heterocyclic benzenesulfonamide derivatives and their molecular docking against dihydrofolate reductase

“…Furthermore, benzenesulfonamides derivatives having aromatic heterocyclic moiety possess a wide spectrum of pharmacological activities, such as anticancer [5][6][7] , anti-bacterial [8][9][10] , anti-inflammatory 11 and anti-viral 12 , hypoglycemic 13 , diuretic 14,15 , anticarbonic anhydrase 16 and anti-thyroid 17 , antimalarial 18 and antileprotic 19,20 activity. In addition, literature survey exhibited that some of the synthesized benzenesulfonamide derivatives were found to be dihydrofolate reductase (DHFR) inhibitors [21][22][23] . On the other hand, the presence of cyanoacetylhydrazono moiety (C¼NÀNÀC(O)ÀCH 2 ÀCN) in a structure, makes it a versatile and convenient intermediate for the synthesis of a wide variety of heterocyclic compounds.…”