{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T14:55:38Z","timestamp":1761058538210},"reference-count":26,"publisher":"American Society for Microbiology","issue":"10","license":[{"start":{"date-parts":[[2006,10,1]],"date-time":"2006-10-01T00:00:00Z","timestamp":1159660800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2006,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            New and improved therapeutics are needed for\n            <jats:italic>Bacillus anthracis<\/jats:italic>\n            , the etiological agent of anthrax. To date, antimicrobial agents have not been developed against the well-validated target dihydrofolate reductase (DHFR). In order to address whether DHFR inhibitors could have potential use as clinical agents against\n            <jats:italic>Bacillus<\/jats:italic>\n            , 27 compounds were screened against this enzyme from\n            <jats:italic>Bacillus cereus<\/jats:italic>\n            , which is identical to the enzyme from\n            <jats:italic>B. anthracis<\/jats:italic>\n            at the active site. Several 2,4-diamino-5-deazapteridine compounds exhibit submicromolar 50% inhibitory concentrations (IC\n            <jats:sub>50<\/jats:sub>\n            s). Four of the inhibitors displaying potency in vitro were tested in vivo and showed a marked growth inhibition of\n            <jats:italic>B. cereus<\/jats:italic>\n            ; the most potent of these has MIC\n            <jats:sub>50<\/jats:sub>\n            and minimum bactericidal concentrations at which 50% are killed of 1.6 \u03bcg\/ml and 0.09 \u03bcg\/ml, respectively. In order to illustrate structure-activity relationships for the classes of inhibitors tested, each of the 27 inhibitors was docked into homology models of the\n            <jats:italic>B. cereus<\/jats:italic>\n            and\n            <jats:italic>B. anthracis<\/jats:italic>\n            DHFR proteins, allowing the development of a rationale for the inhibition profiles. A combination of favorable interactions with the diaminopyrimidine and substituted phenyl rings explains the low IC\n            <jats:sub>50<\/jats:sub>\n            values of potent inhibitors; steric interactions explain higher IC\n            <jats:sub>50<\/jats:sub>\n            values. These experiments show that DHFR is a reasonable antimicrobial target for\n            <jats:italic>Bacillus anthracis<\/jats:italic>\n            and that there is a class of inhibitors that possess sufficient potency and antibacterial activity to suggest further development.\n          <\/jats:p>","DOI":"10.1128\/aac.00386-06","type":"journal-article","created":{"date-parts":[[2006,9,27]],"date-time":"2006-09-27T17:13:29Z","timestamp":1159377209000},"page":"3435-3443","update-policy":"http:\/\/dx.doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":14,"title":["Structure-Activity Relationships of\n            <i>Bacillus cereus<\/i>\n            and\n            <i>Bacillus anthracis<\/i>\n            Dihydrofolate Reductase: toward the Identification of New Potent Drug Leads"],"prefix":"10.1128","volume":"50","author":[{"given":"Tammy M.","family":"Joska","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Dartmouth Medical School, Hanover, New Hampshire 03755"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amy C.","family":"Anderson","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Science, University of Connecticut, Storrs, Connecticut 06269"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.41.11.2406"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.48.12.4643-4649.2004"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/prot.1168"},{"key":"e_1_3_2_5_2","doi-asserted-by":"crossref","first-page":"2227","DOI":"10.1021\/bi00222a028","volume":"30","year":"1991","unstructured":"Bystroff, C., and J. Kraut. 1991. Crystal structure of unliganded Escherichia coli dihydrofolate reductase. Ligand-induced conformational changes and cooperativity in binding. Biochemistry30:2227-2239.","journal-title":"Biochemistry"},{"key":"e_1_3_2_6_2","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1006\/jmbi.2001.4551","volume":"308","year":"2001","unstructured":"Claussen, H., C. Buning, M. Rarey, and T. Lengauer. 2001. FlexE: efficient molecular docking considering protein structure variations. J. Mol. Biol.308:377-395.","journal-title":"J. Mol. Biol."},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.46.12.3843-3845.2002"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.1996.0770"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa012122"},{"key":"e_1_3_2_10_2","doi-asserted-by":"crossref","first-page":"2158","DOI":"10.1021\/jm00012a016","volume":"38","year":"1995","unstructured":"Gangjee, A., F. Mavandadi, S. Queener, and J. McGuire. 1995. Novel 2,4-diamino-5-substituted-pyrrolo[2,3-d]pyrimidines as classical and nonclassical antifolate inhibitors of dihydrofolate reductases. J. Med. Chem.38:2158-2165.","journal-title":"J. Med. 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Synthesis of 2,4-diaminopteridines with bulky lipophilic groups at the 6-position as inhibitors of Pneumocystis carinii,Toxoplasma gondii and mammalian dihydrofolate reductase. Pteridines8:173-187.","journal-title":"Pteridines"},{"key":"e_1_3_2_21_2","doi-asserted-by":"crossref","first-page":"1959","DOI":"10.1002\/jhet.5570330665","volume":"33","year":"1996","unstructured":"Rosowsky, A., C. Mota, and S. Queener. 1996. Brominated trimetrexate analogues as inhibitors of Pneumocystis carinii and Toxoplasma gondii dihydrofolate reductase. J. Heterocycl. Chem.33:1959-1966.","journal-title":"J. Heterocycl. Chem."},{"key":"e_1_3_2_22_2","doi-asserted-by":"crossref","first-page":"3293","DOI":"10.1021\/jo00936a033","volume":"39","year":"1974","unstructured":"Rosowsky, A., and N. Papathanasopoulos. 1974. Quinazolines. XIII. Synthesis of polycyclic 2,4-diaminopyrimidines from aromatic amine hydrochlorides and sodium dicyanamide. J. Org. Chem.39:3293-3295.","journal-title":"J. Org. 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