Dapsone/Pyrimethamine May Prevent Mycobacterial Disease in Immunosuppressed Patients Infected with the Human Immunodeficiency Virus

Opravil, Milos; Péchère, M.; Lazzarin, Adriano; Heald, Alison E.; Rüttimann, S; Iten, Anne; Furrer, Hansjakob; Oertle, Daniel; Praz, G; Vuitton, DA

doi:10.1093/clinids/20.2.244

Cited by 18 publications

(7 citation statements)

References 14 publications

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“…Dapsone-pyrimethamine may prevent mycobacterial disease (M. tuberculosis, M. avium) in immuno-suppressed patients infected with HIV. 3 With very few safe, effective and cheap antimalarial drugs, the problem of parasite resistance has enormous economic and social consequences, particularly in Africa, where malaria causes ca. two million deaths per year and very high levels of morbidity.…”

Section: Introductionmentioning

confidence: 99%

Pyrimethamine analogs as strong inhibitors of double and quadruple mutants of dihydrofolate reductase in human malaria parasites

et al. 2003

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Pyrimethamine acts against malarial parasites by selectively inhibiting their dihydrofolate reductase-thymidylate synthase. Resistance to pyrimethamine in Plasmodium falciparum is due to point mutations in the DHFR domain, initially at residue 108 (S108N), with additional mutations imparting much greater resistance. Our previous work, the development of a simple rational drug design strategy to overcome such resistance, used suitable meta-substituents in the pyrimethamine framework to avoid the unfavorable steric clash with mutant side chains at position 108. Interestingly, the meta-chloro analog of pyrimethamine not only overcame the resistance due to S108N, but also that contributed by the more remote mutation, C59R. The present work improves on this by means of other meta-substituents. Against wild type DHFR, double mutant types A16V + S108T and C59R + S108T, and the highly pyrimethamine/cycloguanil-resistant quadruple-mutant form N51I + C59R + S108N + I164L, pyrimethamine itself gave Ki values of 1.5, 2.4, 72.3 and 859 nM, respectively. The meta-substituted analogs, especially the meta-bromo analog, were much more powerful inhibitors of these DHFRs, including the quadruple-mutant form (meta-bromo analog, Ki 5.1 nM). For comparison, the dihydropyrazine antifolate, WR99210, gave Ki values of 0.9, 3.2, 0.8 and 0.9 nM, respectively. Ki values were also measured against recombinant human DHFR, as were their activities against the growth of Plasmodium falciparum cultures bearing the double mutations (FCB and K1 strains) and quadruple mutation (V1/S) and the wild type (3D7). The meta-analogs were highly active against all of these, with the meta-bromo again being the strongest, having an IC50 of 37 nM against V1/S, compared to > 5000 nM for pyrimethamine itself and 1.1 nM for WR99210.

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Section: Introductionmentioning

confidence: 99%

Pyrimethamine analogs as strong inhibitors of double and quadruple mutants of dihydrofolate reductase in human malaria parasites

et al. 2003

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“…Pyrimethamine also has antibacterial value. Dapsone−pyrimethamine may prevent mycobacterial disease ( Mycobacterium tuberculosis, Mycobacterium avium ) in immunosuppressed patients infected with HIV 1 …”

Section: Introductionmentioning

confidence: 99%

Rational Drug Design Approach for Overcoming Drug Resistance: Application to Pyrimethamine Resistance in Malaria

et al. 1998

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Pyrimethamine acts by selectively inhibiting malarial dihydrofolate reductase-thymidylate synthase (DHFR-TS). Resistance in the most important human parasite, Plasmodium falciparum, initially results from an S108N mutation in the DHFR domain, with additional mutation (most commonly C59R or N51I or both) imparting much greater resistance. From a homology model of the 3-D structure of DHFR-TS, rational drug design techniques have been used to design and subsequently synthesize inhibitors able to overcome malarial pyrimethamine resistance. Compared to pyrimethamine (Ki 1.5 nM) with purified recombinant DHFR fromP. falciparum, the Ki value of the m-methoxy analogue of pyrimethamine was 1.07 nM, but against the DHFR bearing the double mutation (C59R + S108N), the Ki values for pyrimethamine and the m-methoxy analogue were 71.7 and 14.0 nM, respectively. The m-chloro analogue of pyrimethamine was a stronger inhibitor of both wild-type DHFR (with Ki 0.30 nM) and the doubly mutant (C59R +S108N) purified enzyme (with Ki 2.40 nM). Growth of parasite cultures of P. falciparum in vitro was also strongly inhibited by these compounds with 50% inhibition of growth occurring at 3.7 microM for the m-methoxy and 0.6 microM for the m-chloro compounds with the K1 parasite line bearing the double mutation (S108N + C59R), compared to 10.2 microM for pyrimethamine. These inhibitors were also found in preliminary studies to retain antimalarial activity in vivo in P. berghei-infected mice.

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“…However dapsone/pyrimethamine more effectively prevented infections with Pneumocystis carinii and Toxoplasma gondii than aerosolized pentamidine [41]. Moreover, a subanalysis of the results of this study reveals a slight, nonsignificant trend indicating that this regimen may provide an additional prophylactic effect against atypical mycobacterial infections [42].…”

Section: Primary and Secondary Prophylaxis For Pneumocystis Carinii Rmentioning

confidence: 63%

Primary and secondary prophylaxis for Pneumocystis carinii related complications in HIV patients

Held¹,

Goebel²

1996

Eur Respir J

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Dapsone/Pyrimethamine May Prevent Mycobacterial Disease in Immunosuppressed Patients Infected with the Human Immunodeficiency Virus

Cited by 18 publications

References 14 publications

Pyrimethamine analogs as strong inhibitors of double and quadruple mutants of dihydrofolate reductase in human malaria parasites

Pyrimethamine analogs as strong inhibitors of double and quadruple mutants of dihydrofolate reductase in human malaria parasites

Rational Drug Design Approach for Overcoming Drug Resistance: Application to Pyrimethamine Resistance in Malaria

Primary and secondary prophylaxis for Pneumocystis carinii related complications in HIV patients

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