Pneumocystis carinii Dihydropteroate Synthase but Not Dihydrofolate Reductase Gene Mutations Correlate with Prior Trimethoprim‐Sulfamethoxazole or Dapsone Use

Ma, Liang; Borio, Luciana; Masur, Henry; Kovacs, Joseph A.

doi:10.1086/315148

Cited by 169Pneumocystis jirovecii pneumonia detection and treatmentPneumonia and Respiratory InfectionsAntibiotic Resistance in Bacteria

Pneumocystis carinii Dihydropteroate Synthase but Not Dihydrofolate Reductase Gene Mutations Correlate with Prior Trimethoprim‐Sulfamethoxazole or Dapsone Use

Ma, Liang, Borio, Luciana, Masur, Henry, Kovacs, Joseph A.·1999·The Journal of Infectious Diseases

DOI 10.1086/315148

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Abstract

Recent studies of the human Pneumocystis carinii dihydropteroate synthase (DHPS) gene suggest that P. carinii is developing resistance to sulfamethoxazole (SMX) and dapsone.To explore whether P. carinii is also developing resistance to trimethoprim (TMP), the human P. carinii dihydrofolate reductase (DHFR) gene was cloned, DHFR and DHPS genes in 37 P. carinii isolates from 35 patients were sequenced, and the relationship between TMP-SMX or dapsone use and gene mutations was analyzed.The DHFR gene sequences were identical in all isolates except 1 with a synonymous substitution.In contrast, the DHPS gene sequences showed mutations in 16 of the 37 isolates; prior sulfa/sulfone prophylaxis was associated with the presence of these mutations ().In addition to suggesting that there is less selective P !.001pressure on DHFR than on DHPS, this study reinforces the hypothesis that mutations in the DHPS gene are likely involved in the development of sulfa resistance in P. carinii.The combination of trimethoprim (TMP) and sulfamethoxazole (SMX) serves as the first-line therapeutic and prophylactic regimen for pneumonia caused by Pneumocystis carinii, which remains a major opportunistic agent in patients infected with human immunodeficiency virus (HIV) and in other immunocompromised patients.This combination inhibits 2 key enzymes in folate metabolism.Dapsone is another commonly used prophylactic agent, and, like SMX, it targets the enzyme dihydropteroate synthase (DHPS), which catalyzes the condensation of para-aminobenzoic acid with 7,8-dihydropterin-pyrophosphate (DHPPP), forming 7,8-dihydropteroate.TMP acts on dihydrofolate reductase (DHFR), which catalyzes the reduction of dihydrofolate to tetrahydrofolate and is dependent on the reduced form of nicotinamide adenine dinucleotide phosphate.The widespread use of DHFR and DHPS inhibitors in antimicrobial chemotherapy has resulted in the emergence of antifolate drug resistance in numerous bacteria and some protozoa [1-10], raising concerns that similar resistance would develop

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Two studies have failed to demonstrate an association between the use of TMP-SMX for PCP prophylaxis in HIV-infected persons and the presence of DHFR gene mutations.
“To date, two studies have failed to demonstrate an association between the use of TMP-SMX for PCP prophylaxis in HIV-infected persons and the presence of DHFR gene mutations (21,36).”
From Dihydropteroate Synthase Gene Mutations inPneumocystisand Sulfa Resistance (2004) · cites this paper as [21]
Sulfa medications appear to exert selective pressure on Pneumocystis, as the DHPS gene is more likely to display mutations in highly conserved regions in patients with PCP who have previously been exposed to sulfa medications.
“Sulfa medications appear to exert selective pressure on Pneumocystis (18), as the DHPS gene is more likely to display mutations in highly conserved regions in patients with PCP who have previously been exposed to sulfa medications (19–25).”
From Dihydropteroate Synthase Gene Mutations inPneumocystisand Sulfa Resistance (2004) · cites this paper as [21]
Seven of the nine studies found that most HIV-infected patients with a diagnosis of PCP who had been prescribed TMP-SMX or dapsone for PCP prophylaxis had Pneumocystis that contained DHPS mutations (range 19%-80%).
“Nevertheless, seven of the nine studies found that most HIV-infected patients with a diagnosis of PCP who had been prescribed TMP-SMX or dapsone for PCP prophylaxis had Pneumocystis that contained DHPS mutations (range 19%–80%, Table 2) (19–24,30).”
From Dihydropteroate Synthase Gene Mutations inPneumocystisand Sulfa Resistance (2004) · cites this paper as [21]
Several studies have consistently demonstrated a significant association between the use of TMP-SMX or dapsone for PCP prophylaxis in HIV-infected persons and the presence of DHPS gene mutations.
“Several studies have consistently demonstrated a significant association between the use of TMP-SMX or dapsone for PCP prophylaxis in HIV-infected persons and the presence of DHPS gene mutations (Table 2) (19–25,30).”
From Dihydropteroate Synthase Gene Mutations inPneumocystisand Sulfa Resistance (2004) · cites this paper as [21]
Based on homology to the E. coli DHPS, these point mutations appear to be in an active site of the enzyme involved in substrate binding; thus, amino acid substitutions in these regions could result in structural changes that could interfere with substrate binding and enzyme activity.
“Based on homology to the E. coli DHPS, these point mutations appear to be in an active site of the enzyme involved in substrate binding; thus, amino acid substitutions in these regions could result in structural changes that could interfere with substrate binding and enzyme activity (21).”
From Dihydropteroate Synthase Gene Mutations inPneumocystisand Sulfa Resistance (2004) · cites this paper as [21]

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Mutations in the Dihydropteroate Synthase Gene of Human‐DerivedPneumocystis cariniiIsolates from Italy Are Infrequent but Correlate with Prior Sulfa Prophylaxis
Ma, L., Kovacs, J. A., Cargnel, A., Valerio, A., Fantoni, G., & Atzori, C. (2002) · The Journal of Infectious Diseases · doi:10.1086/340220 · Cited by 61 · see citing works
Self-citation
Absence of mutations associated with sulfa resistance in Pneumocystis carinii dihydropteroate synthase gene from non-human primates.
Demanche, C., Guillot, J., Berthelemy, M., Petit, T., Roux, P., & Wakefield, A. E. (2002) · Medical Mycology · doi:10.1080/714031111 · Cited by 13 · see citing works

Authors: Ma, L., Borio, L., Masur, H., & Kovacs, J. A.
Affiliations: National Institutes of Health (US)
ORCID: Ma, Liang
Masur, Henry
Kovacs, Joseph A.
Venue: The Journal of Infectious Diseases
Publisher: Oxford University Press (OUP)
Published: 1999-12
Volume: 180
Issue: 6
Pages: 1969-1978
ISSN: 0022-1899 (ISSN-L)
1537-6613
DOI: 10.1086/315148
OpenAlex: W1997907868
Cited by: 169
References: 44
Citations by year: 2026: 1 · 2025: 2 · 2024: 2 · 2023: 2 · 2022: 2 · 2021: 4 · 2020: 2 · 2019: 6 · 2018: 5 · 2017: 3 · 2016: 7 · 2015: 6 · 2014: 5 · 2013: 6 · 2012: 6
FWCI: 9.00
Type: journal article
Language: en
Open access: closed
Locations: The Journal of Infectious Diseases (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Epidemiology › Pneumocystis jirovecii pneumonia detection and treatment
Health Sciences › Medicine › Epidemiology › Pneumonia and Respiratory Infections
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Antibiotic Resistance in Bacteria
Keywords: Pneumocystis carinii, dihydropteroate synthase, dihydrofolate reductase, sulfamethoxazole resistance, trimethoprim-sulfamethoxazole, dapsone, antifolate resistance, prophylaxis, HIV-associated pneumonia, opportunistic infections
MeSH terms: Amino Acid Sequence, Animals, Anti-Infective Agents, Cloning, Molecular, Dapsone, Dihydropteroate Synthase, Drug Resistance, Microbial, Genes, Fungal, Humans, Molecular Sequence Data, Mutation, Pneumocystis, Pneumonia, Pneumocystis, Tetrahydrofolate Dehydrogenase, Trimethoprim, Sulfamethoxazole Drug Combination, Sequence Alignment, Sequence Analysis, DNA, Rats

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Pneumocystis carinii Dihydropteroate Synthase but Not Dihydrofolate Reductase Gene Mutations Correlate with Prior Trimethoprim‐Sulfamethoxazole or Dapsone Use

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