Enhanced in vitro activity of WR99210 in combination with dapsone against Mycobacterium avium complex

Shah, Lisa M.; DeStefano, Michelle S.; Cynamon, Michael H.

doi:10.1128/aac.40.11.2644

Cited by 10 publications

(6 citation statements)

References 7 publications

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“…PS-15 plus dapsone appeared to be effective only against P. carinii and T. gondii infections, confirming previous observations (10). No significant activity against the M. avium complex was observed, which is in contrast to the observations made in vitro by other teams (28,37).…”

Section: Discussionsupporting

confidence: 87%

Drug Evaluation of Concurrent Pneumocystis carinii , Toxoplasma gondii , and Mycobacterium avium Complex Infections in a Rat Model

Brun-Pascaud

Rajagopalan-Levasseur

Chau

et al. 1998

Antimicrob Agents Chemother

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We present a new experimental model for the simultaneous evaluation of the activities of drugs against Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium complex infections. Rats latently infected withP. carinii were challenged with the MO-1 strain ofM. avium and then immunosuppressed with corticosteroids for 7 weeks. At week 5 the RH strain of T. gondii was intraperitoneally injected. Organs were examined for the three pathogens after death or killing of the animals at week 7. Without treatment, rats challenged with T. gondii died with pulmonary P. carinii infection and disseminatedT. gondii and M. avium infections. In order to assess the value of the model for evaluation of the activities of drugs, we administered by oral gavage for 7 weeks drugs or combinations of drugs selected for their individual efficacies against at least one pathogen. We found that clarithromycin with sulfamethoxazole, clarithromycin with atovaquone, roxithromycin with sulfamethoxazole or dapsone, and rifabutin with atovaquone were effective against the three infections, whereas PS-15 with dapsone and trimethoprim with sulfamethoxazole were active against Toxoplasma andPneumocystis infections only. This triple-infection rat model offers a new tool for the simultaneous evaluation of the activities of drugs against three of the major opportunistic infections occurring in immunosuppressed individuals.

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Section: Discussionsupporting

confidence: 87%

Drug Evaluation of Concurrent Pneumocystis carinii , Toxoplasma gondii , and Mycobacterium avium Complex Infections in a Rat Model

Brun-Pascaud

Rajagopalan-Levasseur

Chau

et al. 1998

Antimicrob Agents Chemother

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“…Trimethoprim targets DHFR and inhibits bacterial growth in a bacteriostatic manner. In addition to Trimethoprim, small molecules such as lipophilic deazapteridine and antimalarial lead WR99210 have also been identified as DHFR inhibitors . Para‐aminosalicylic acid (PAS), a second line TB drug, also inhibits folate biosynthetic pathway of M. tuberculosis .…”

Section: Screening Approachesmentioning

confidence: 99%

Recent advances for identification of new scaffolds and drug targets for Mycobacterium tuberculosis

Dhiman

Singh

2018

IUBMB Life

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Tuberculosis (TB) is a leading cause of mortality and morbidity with an estimated 1.7 billion people latently infected with the pathogen worldwide. Clinically, TB infection presents itself as an asymptomatic infection, which gradually manifests to life threatening disease. The emergence of various drug resistant strains of Mycobacterium tuberculosis and lengthy duration of chemotherapy are major challenges in the field of TB drug development. Hence, there is an urgent need to develop scaffolds that possess a novel mechanism of action, can shorten the duration of therapy, and are active against both drug resistant and susceptible strains. In this review, we will discuss recent progress made in the field of TB drug development with emphasis on screening methods and drug targets from M. tuberculosis. The current review provides insights into mechanism of action of new scaffolds that are being evaluated in various stages of clinical trials. © 2018 IUBMB Life, 70(9):905-916, 2018.

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“…Combinations of trimethoprim-dapsone and trimethoprim-sulfamethoxazole have been used for the treatment of Pneumocystis carinii pneumonia (2)(3)(4). Folate antagonists have also been shown to have in vitro activity against mycobacteria (7)(8)(9).…”

mentioning

confidence: 99%

“…Several of these isolates had been tested previously for their in vitro susceptibilities to two other DHFR inhibitors, PYR and WR99210 (8,9). The MIC 50 and MIC 90 of PYR were each 32 g/ml, and those of WR99210 were 2 and 8 g/ml, respectively.…”

mentioning

confidence: 99%

In Vitro Activities of Several Diaminomethylpyridopyrimidines against Mycobacterium avium Complex

Shoen¹,

Choromanska²,

Reynolds

et al. 1998

Antimicrob Agents Chemother

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Three recently synthesized dihydrofolate reductase (DHFR) inhibitors designated SoRI 8890, 8895, and 8897 were evaluated for their in vitro activities against 25 isolates of Mycobacterium avium complex. The MICs at which 50 and 90% of isolates were inhibited were 1 and 2, 4 and 8, and 4 and 8 μg/ml for SoRI 8890, 8895, and 8897, respectively. Although the addition of dapsone at 0.5 μg/ml did not significantly enhance the in vitro activities of these compounds, their activities alone were comparable to, if not better than, results seen with other DHFR inhibitors, such as pyrimethamine or WR99210.

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Enhanced in vitro activity of WR99210 in combination with dapsone against Mycobacterium avium complex

Cited by 10 publications

References 7 publications

Drug Evaluation of Concurrent Pneumocystis carinii , Toxoplasma gondii , and Mycobacterium avium Complex Infections in a Rat Model

Drug Evaluation of Concurrent Pneumocystis carinii , Toxoplasma gondii , and Mycobacterium avium Complex Infections in a Rat Model

Recent advances for identification of new scaffolds and drug targets for Mycobacterium tuberculosis

In Vitro Activities of Several Diaminomethylpyridopyrimidines against Mycobacterium avium Complex

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