In vitro susceptibility of clinical isolates of Mycobacterium avium and M. intracellulare to folate antagonists

Raszka, William V.; Skillman, Laurie P.; McEvoy, Peter

doi:10.1016/0732-8893(94)90092-2

Cited by 7 publications

(5 citation statements)

References 9 publications

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“…However the infection was found subsided when treated with azithromycin or clarithromycin together with ethambutol [6, 105]. Further, the M. avium isolates have been demonstrated to get inhibited by sufficient concentrations of sulfamethoxazole in serum [106]. Rifabutin prophylaxis may also help in controlling the disseminated infection [93].…”

Section: Mycobacterium Avium: the Zoonotic Implicationsmentioning

confidence: 99%

Tuberculosis in Birds: Insights into theMycobacterium aviumInfections

Dhama

Mahendran

Tiwari

et al. 2011

Veterinary Medicine International

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Tuberculosis, a List B disease of World Organization for Animal Health, caused by M. avium or M. genavense predominantly affects poultry and pet or captive birds. Clinical manifestations in birds include emaciation, depression and diarrhea along with marked atrophy of breast muscle. Unlike tuberculosis in animals and man, lesions in lungs are rare. Tubercular nodules can be seen in liver, spleen, intestine and bone marrow. Granulomatous lesion without calcification is a prominent feature. The disease is a rarity in organized poultry sector due to improved farm practices, but occurs in zoo aviaries. Molecular techniques like polymerase chain reaction combined with restriction fragment length polymorphism and gene probes aid in rapid identification and characterization of mycobacteria subspecies, and overcome disadvantages of conventional methods which are slow, labour intensive and may at times fail to produce precise results. M. avium subsp. avium with genotype IS901+ and IS1245+ causes infections in animals and human beings too. The bacterium causes sensitivity in cattle to the tuberculin test. The paper discusses in brief the M. avium infection in birds, its importance in a zoonotic perspective, and outlines conventional and novel strategies for its diagnosis, prevention and eradication in domestic/pet birds and humans alike.

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Section: Mycobacterium Avium: the Zoonotic Implicationsmentioning

confidence: 99%

Tuberculosis in Birds: Insights into theMycobacterium aviumInfections

Dhama

Mahendran

Tiwari

et al. 2011

Veterinary Medicine International

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“…Here, we have investigated the enzyme 6-hydroxymethyl-7,8-dihydropteroate synthase (DHPS, EC 2.5.1.15) from M. tuberculosis in order to explore the possibilities this protein gives for the design of anti-TB drugs. Diaminodiphenylsulfone or dapsone (Figure 1), a sulfone inhibitor of DHPS, has been clinically used for decades to treat leprosy, which is caused by the related organism Mycobacterium leprae (Anand, 1996), and sulfamethoxazole ( Figure 1) has been shown to have in vitro effects against Mycobacterium avium and Mycobacterium intracellulare (Raszka et al, 1994). M. tuberculosis DHPS is very similar to M. leprae DHPS (79 % sequence identity) and Mycobacterium avium DHPS (81 % sequence identity) (preliminary sequence data from The Institute for Genomic Research).…”

Section: Introductionmentioning

confidence: 99%

Crystal structure of Mycobacterium tuberculosis 6-hydroxymethyl-7,8-dihydropteroate synthase in complex with pterin monophosphate: new insight into the enzymatic mechanism and sulfa-drug action 1 1Edited by I. Wilson

Baca

Sirawaraporn

Turley

et al. 2000

Journal of Molecular Biology

122

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“…In summary, the compound in Table 1 with the best combination of potency and selectivity against Pc DHFR was the 5′-(3-carboxyphenyl)ethynyl analogue 28. In terms of the distance separating the COOH group from the phenyl ring, 28 was intuitively viewed as an analogue of 2,4-diamino-5-[2′-methoxy-5′-(4-carboxy-1pentynyl)benzyl]pyrimidine (15), whose IC 50 against Pc and rat DHFR was previously reported to be 28 and 2200 nM, respectively. 3 It thus appears that replacement of the three CH 2 groups in the side chain of this compound with a phenyl ring was favorable for binding to both enzymes but unfortunately was more favorable for binding to the rat enzyme, resulting in lower selectivity.…”

Section: Enzyme Inhibition Assaysmentioning

confidence: 97%

“…Since 2 μg/mL is generally considered a physiologically achievable concentration, these compounds could have therapeutic utility in the treatment of disseminated M. avium infection. Interestingly, trimethoprim by itself is reported to be ineffective against human isolates of M. avium even at a concentration of up to 1.5 μg/mL, although there is at least one report that it is clinically effective against M. avium infection when combined with sulfamethoxazole . It may be noted that, while their in vitro molar equivalent potency is considerably lower than that of several popular macrolide and quinolone antibiotics, ,, the antifolate activity of 12 , 13 , and 16 would probably not be affected by macrolide resistance, an emergent problem in the clinical management of M. avium infection .…”

Section: Enzyme Inhibition Assaysmentioning

confidence: 99%

“…Like trimethoprim, the compounds that provided the impetus for the present work were 2,4-diamino-5-(substituted benzyl)pyrimidines; however, as with piritrexim but in contrast to trimethoprim, the benzyl group was 2′,5′-disubstituted rather than 3′,4′,5′-trisubstituted. Furthermore, while the 2′-methoxy group of piritrexim was retained, the 5′-substituent consisted of either a hydrophobic long-chain alkoxy group (3)(4)(5)(6)(7) or various water-solubilizing ω-carboxyalkoxy (8)(9)(10)(11)(12)(13), ω-carboxyalkynyl (14)(15)(16), ω-carboxyalkyl (17)(18)(19), carboxybenzyloxy (20,21), or carboxyphenoxypropynyl (22,23) groups. The structures of trimethoprim and 2,4-diamino-5-(2′,5′-substituted benzyl)pyrimidines 2-23 are shown in Figure 1.…”

Section: Introductionmentioning

confidence: 99%

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New 2,4-Diamino-5-(2‘,5‘-substituted benzyl)pyrimidines as Potential Drugs against Opportunistic Infections of AIDS and Other Immune Disorders. Synthesis and Species-Dependent Antifolate Activity

et al. 2004

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In a continuing effort to design small-molecule inhibitors of dihydrofolate reductase (DHFR) that combine the enzyme-binding selectivity of 2,4-diamino-5-(3',4',5'-trimethoxybenzyl)pyrimidine (trimethoprim, TMP) with the potency of 2,4-diamino-5-methyl-6-(2',5'-dimethoxybenzyl)pyrido[2,3-d]pyrimidine (piritrexim, PTX), seven previously undescribed 2,4-diamino-5-[2'-methoxy-5'-(substituted benzyl)]pyrimidines were synthesized in which the substituent at the 5'-position was a carboxyphenyl group linked to the benzyl moiety by a bridge of two or four atoms in length. The new analogues were all obtained from 2,4-diamino-5-(5'-iodo-2'-methoxybenzyl)pyrimidine via a Sonogashira reaction, followed, where appropriate, by catalytic hydrogenation. The new analogues were tested as inhibitors of DHFR from Pneumocystis carinii (Pc), Toxoplasma gondii (Tg), and Mycobacterium avium (Ma), three life-threatening pathogens often found in AIDS patients and individuals whose immune system is impaired as a result of treatment with immunosuppressive chemotherapy or radiation. The selectivity index (SI) of each compound was obtained by dividing its 50% inhibitory concentration (IC(50)) against Pc, Tg, or Ma DHFR by its IC(50) against rat DHFR. 2,4-Diamino-[2'-methoxy-5'-(3-carboxyphenyl)ethynylbenzyl]pyrimidine (28), with an IC(50) of 23 nM and an SI of 28 in the Pc DHFR assay, had about the same potency as PTX and was 520 times more potent than TMP. As an inhibitor of Tg DHFR, 28 had an IC(50) of 5.5 nM (510-fold lower than that of TMP and similar to that of PTX) and an SI value of 120 (2-fold better than TMP and vastly superior to PTX). Against Ma DHFR, 28 had IC(50) and SI values of 1.5 nM and 430, respectively, compared with 300 nM and 610 for TMP. Although it had 2.5-fold lower potency than 28 against Ma DHFR (IC(50) = 3.7 nM) and was substantially weaker against Pc and Tg DHFR, 2,4-diamino-[2'-methoxy-5'-(4-carboxyphenyl)ethynylbenzyl]pyrimidine (29), with the carboxy group at the para rather than the meta position, displayed 2200-fold selectivity against the Ma enzyme and was the most selective 2,4-diamino-5-(5'-substituted benzyl)pyrimidine inhibitor of this enzyme we have encountered to date. Additional bioassay data for these compounds are also reported.

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In vitro susceptibility of clinical isolates of Mycobacterium avium and M. intracellulare to folate antagonists

Cited by 7 publications

References 9 publications

Tuberculosis in Birds: Insights into theMycobacterium aviumInfections

Tuberculosis in Birds: Insights into theMycobacterium aviumInfections

Crystal structure of Mycobacterium tuberculosis 6-hydroxymethyl-7,8-dihydropteroate synthase in complex with pterin monophosphate: new insight into the enzymatic mechanism and sulfa-drug action 1 1Edited by I. Wilson

New 2,4-Diamino-5-(2‘,5‘-substituted benzyl)pyrimidines as Potential Drugs against Opportunistic Infections of AIDS and Other Immune Disorders. Synthesis and Species-Dependent Antifolate Activity

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