Dihydropteroate Synthase and Novel Dihydrofolate Reductase Gene Mutations in Strains of
            <i>Pneumocystis jirovecii</i>
            from South Africa

Robberts, Lourens; Chalkley, L. J.; Weyer, Karin; Goussard, P; Liebowitz, Lynne D.

doi:10.1128/jcm.43.3.1443-1444.2005

Cited by 27 publications

(19 citation statements)

References 19 publications

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“…The small sample sizes and relatively low frequencies among these studies preclude any conclusions about trends in prevalence over time. The overall prevalence of P. jirovecii DHPS mutations in China is similar to those reported from other developing countries (3,(8)(9)(10)(11)(12) but lower than those reported from developed countries (1-4) and may reflect the less frequent utilization of TMP-SMX or dapsone for PCP prophylaxis in developing countries.…”

supporting

confidence: 53%

“…This is similar to the prevalences reported in other Asian countries, including Japan (13) and Thailand (9), where approximately 60% of samples harbored nucleotide changes in the DHFR gene, most of which were synonymous. However, this prevalence is higher than those reported in the United States (3%, all synonymous [2]), South Africa (15%, all nonsynonymous [8]), Uganda (8%, all synonymous [10]), and Portugal (27% overall, of which 4% were nonsynonymous [14]). None of these studies linked nucleotide changes in the DHFR gene to antifolate prophylaxis for PCP, and given that the vast majority of the nucleotide changes are synonymous, they likely represent polymorphisms rather than antibiotic-related mutations.…”

contrasting

confidence: 41%

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Mutational Analysis of Pneumocystis jirovecii Dihydropteroate Synthase and Dihydrofolate Reductase Genes in HIV-Infected Patients in China

Deng

Li²,

Lan

et al. 2014

J Clin Microbiol

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supporting

confidence: 53%

contrasting

confidence: 41%

Mutational Analysis of Pneumocystis jirovecii Dihydropteroate Synthase and Dihydrofolate Reductase Genes in HIV-Infected Patients in China

Deng

Li²,

Lan

et al. 2014

J Clin Microbiol

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“…We found that 56% of patients with PCP were infected with mutant P. jirovecii strains. This proportion stands in contrast to the lower frequencies reported from the African continent and other countries outside the industrialized world (8,12,23,25,30,34,40,46,48). The risk that P. jirovecii will develop mutations in the DHPS gene is higher for patients with PCP receiving sulfa drug prophylaxis than for those not receiving it (5,15,16,22,26,32,38).…”

Section: Discussioncontrasting

confidence: 49%

“…In South Africa, a few studies that screened specimens from limited numbers of adults and children have reported mostly low mutation rates (8,12,34,48). Here we present the results of a large laboratory-based study aimed at ascertaining the prevalence in South Africa of P. jirovecii strains harboring mutations at positions 165 and 171 in the fas gene.…”

mentioning

confidence: 97%

High Prevalence of Dihydropteroate Synthase Mutations in Pneumocystis jirovecii Isolated from Patients with Pneumocystis Pneumonia in South Africa

et al. 2010

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Pneumocystis jirovecii pneumonia (PCP) is an important cause of morbidity and mortality in immunocompromised patients. Sulfa-containing drugs are used for the treatment and prophylaxis of PCP. Mutations in the P. jirovecii fas gene, which encodes dihydropteroate synthase (DHPS), are associated with prior exposure to sulfa drugs, and their appearance suggests the emergence of variants with reduced sulfa susceptibility. The present study examined the prevalence of DHPS mutations in P. jirovecii strains isolated from South African patients with PCP. P. jirovecii infection was investigated by immunofluorescence microscopy and quantitative real-time PCR with respiratory specimens from 712 patients (93% of whom were >15 years of age) with suspected PCP consecutively received for the detection of P. jirovecii over 1 year. PCR amplification and sequencing of the DHPS fas gene was attempted with DNA from the P. jirovecii-positive samples. P. jirovecii infection was confirmed by immunofluorescence microscopy in 168/712 (24%) of the patients. Carriage of the fungus was revealed by real-time PCR in 17% of the patients with negative microscopy results. The P. jirovecii fas gene was successfully amplified from specimens from 151 patients and sequenced. Mutations resulting in the Thr55Ala and/or Pro57Ser amino acid substitution were detected in P. jirovecii strains from 85/151 (56%) patients. The high frequency of PCP episodes with P. jirovecii harboring DHPS mutations in South Africa indicates that populations of this fungus are evolving under the considerable selective pressure exerted by sulfa-containing antibiotics. These results, similar to previous observations of sulfa drug resistance in bacterial populations, underscore the importance of the rational use of sulfa medications either prophylactically against PCP or for the treatment of other infections.

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“…Mutations leading to amino acid substitutions in DHPS have been linked to resistance to sulfamethoxazole (1). Mutations leading to amino acid substitutions in dihydrofolate reductase of Pneumocystis jirovecii have also been observed worldwide for over a decade, but attempts to link clinical outcomes to these mutations have been inconclusive (2)(3)(4)(5)(6)(7)(8)(9)(10).…”

mentioning

confidence: 99%

Trimethoprim Resistance of Dihydrofolate Reductase Variants from Clinical Isolates of Pneumocystis jirovecii

Queener

Cody

Pace

et al. 2013

Antimicrob Agents Chemother

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dPneumocystis jirovecii is an opportunistic pathogen that causes serious pneumonia in immunosuppressed patients. Standard therapy and prophylaxis include trimethoprim (TMP)-sulfamethoxazole; trimethoprim in this combination targets dihydrofolate reductase (DHFR). Fourteen clinically observed variants of P. jirovecii DHFR were produced recombinantly to allow exploration of the causes of clinically observed failure of therapy and prophylaxis that includes trimethoprim. Six DHFR variants (S31F, F36C, L65P, A67V, V79I, and I158V) showed resistance to inhibition by trimethoprim, with K i values for trimethoprim 4-fold to 100-fold higher than those for the wild-type P. jirovecii DHFR. An experimental antifolate with more conformational flexibility than trimethoprim showed strong activity against one trimethoprim-resistant variant. The two variants that were most resistant to trimethoprim (F36C and L65P) also had increased K m values for dihydrofolic acid (DHFA). The catalytic rate constant (k cat ) was unchanged for most variant forms of P. jirovecii DHFR but was significantly lowered in F36C protein; one naturally occurring variant with two amino acid substitutions (S106P and E127G) showed a doubling of k cat , as well as a K m for NADPH half that of the wild type. The strongest resistance to trimethoprim occurred with amino acid changes in the binding pocket for DHFA or trimethoprim, and the strongest effect on binding of NADPH was linked to a mutation involved in binding the phosphate group of the cofactor. This study marks the first confirmation that naturally occurring mutations in the gene for DHFR from P. jirovecii produce variant forms of DHFR that are resistant to trimethoprim and may contribute to clinically observed failures of standard therapy or prophylaxis.

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Dihydropteroate Synthase and Novel Dihydrofolate Reductase Gene Mutations in Strains of Pneumocystis jirovecii from South Africa

Cited by 27 publications

References 19 publications

Mutational Analysis of Pneumocystis jirovecii Dihydropteroate Synthase and Dihydrofolate Reductase Genes in HIV-Infected Patients in China

Mutational Analysis of Pneumocystis jirovecii Dihydropteroate Synthase and Dihydrofolate Reductase Genes in HIV-Infected Patients in China

High Prevalence of Dihydropteroate Synthase Mutations in Pneumocystis jirovecii Isolated from Patients with Pneumocystis Pneumonia in South Africa

Trimethoprim Resistance of Dihydrofolate Reductase Variants from Clinical Isolates of Pneumocystis jirovecii

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