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

Shah, Lisa M.; Meyer, Sophie; Cynamon, Michael H.

doi:10.1128/aac.40.10.2426

Cited by 4 publications

(3 citation statements)

References 7 publications

(5 reference statements)

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“…It has well-defined in vivo inhibitory action against Mycobacterium leprae, the causative agent of leprosy. Dapsone also has been reported to be effective against different mycobacteria strains such as M. avium and Mtb [15][16][17]. Intended use against Mtb was studded recently where Poly lactic-co-glycolic acid (PLGA) nanoparticles were used as a delivery system of dapsone in combination with clofazimine [18].…”

Section: Resultsmentioning

confidence: 99%

Cholesterol-dependent activity of dapsone against non-replicating persistent mycobacteria

et al. 2022

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One-third of the world’s population is estimated to be latently infected with Mycobacterium tuberculosis . This reservoir of bacteria is largely resistant to antimicrobial treatment that often only targets actively replicating mycobacteria, with current treatment for latent infection revolving around inhibiting the resuscitation event rather than preventing or treating latent infection. As a result, antimicrobials that target latent infection often have little to no activity in vivo. Here we report a method of in vitro analysis of physiologically relevant non-replicating persistence (NRP) utilizing cholesterol as the sole carbon source, alongside hypoxia as a driver of Mycobacterium bovis BCG into the NRP state. Using the minimal cholesterol media NRP assay, we observed an increased state of in vitro resistance to front-line anti-tubercular compounds. However, following a phenotypic screen of an approved-drug library, we identified dapsone as a bactericidal active molecule against cholesterol-dependent NRP M. bovis BCG. Through an overexpression trial of probable antimicrobial target enzymes, we further identified FolP2, a non-functional dihydropteroate synthase homologue, as the likely target of dapsone under cholesterol-NRP due to a significant increase in bacterial resistance when overexpressed. These results highlight the possible reason for little in vivo activity seen for current front-line anti-NRP drugs, and we introduce a new methodology for future drug screening as well as a potential role for dapsone inclusion within the current treatment regime.

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Section: Resultsmentioning

confidence: 99%

Cholesterol-dependent activity of dapsone against non-replicating persistent mycobacteria

et al. 2022

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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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Structure-based design, synthesis and preliminary evaluation of selective inhibitors of dihydrofolate reductase from Mycobacterium tuberculosis

El-Hamamsy

Smith

Thompson

et al. 2007

Bioorganic & Medicinal Chemistry

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Tuberculosis is an increasing threat, owing to the spread of AIDS and to the development of resistance of the causative organism, Mycobacterium tuberculosis, to the currently available drugs. Dihydrofolate reductase (DHFR) is an important enzyme of the folate cycle; inhibition of DHFR inhibits growth and causes cell death. The crystal structure of M. tuberculosis DHFR revealed a glycerol tightly bound close to the binding site for the substrate dihydrofolate; this glycerol-binding motif is absent from the human enzyme. A series of pyrimidine-2,4-diamines was designed with a two-carbon tether between a glycerol-mimicking triol and the 6-position of the heterocycle; these compounds also carried aryl substituents at the 5-position. These, their diastereoisomers, analogues lacking two hydroxy groups and analogues lacking the two-carbon spacing linker were synthesised by acylation of the anions derived from phenylacetonitriles with ethyl (4S,5R)-4-benzyloxymethyl-2,2-dimethyl-1,3-dioxolane-4-propanoate, ethyl (4S,5S)-4-benzyloxymethyl-2,2-dimethyl-1,3-dioxolane-4-propanoate, tetrahydrooxepin-2-one and 2,3-O-isopropylidene-d-erythronolactone, respectively, to give the corresponding alpha-acylphenylacetonitriles. Formation of the methyl enol ethers, condensation with guanidine and deprotection gave the pyrimidine-2,4-diamines. Preliminary assay of the abilities of these compounds to inhibit the growth of TB5 Saccharomyces cerevisiae carrying the DHFR genes from M. tuberculosis, human and yeast indicated that 5-phenyl-6-((3R,4S)-3,4,5-trihydroxypentyl)pyrimidine-2,4-diamine selectively inhibited M. tuberculosis DHFR and had little effect on the human or yeast enzymes.

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

Cited by 4 publications

References 7 publications

Cholesterol-dependent activity of dapsone against non-replicating persistent mycobacteria

Cholesterol-dependent activity of dapsone against non-replicating persistent mycobacteria

In Vitro Activities of Several Diaminomethylpyridopyrimidines against Mycobacterium avium Complex

Structure-based design, synthesis and preliminary evaluation of selective inhibitors of dihydrofolate reductase from Mycobacterium tuberculosis

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