{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T18:12:54Z","timestamp":1793729574707,"version":"4.6.1"},"reference-count":153,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2014,1,21]],"date-time":"2014-01-21T00:00:00Z","timestamp":1390262400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibiotics"],"abstract":"<jats:p>The need for new antimicrobials is great in face of a growing pool of resistant pathogenic organisms. This review will address the potential for antimicrobial therapy based on polypharmacological activities within the currently utilized bacterial biosynthetic folate pathway. The folate metabolic pathway leads to synthesis of required precursors  for cellular function and contains a critical node, dihydrofolate reductase (DHFR), which  is shared between prokaryotes and eukaryotes. The DHFR enzyme is currently targeted  by methotrexate in anti-cancer therapies, by trimethoprim for antibacterial uses, and  by pyrimethamine for anti-protozoal applications. An additional anti-folate target is dihyropteroate synthase (DHPS), which is unique to prokaryotes as they cannot acquire folate through dietary means. It has been demonstrated as a primary target for the longest standing antibiotic class, the sulfonamides, which act synergistically with DHFR inhibitors. Investigations have revealed most DHPS enzymes possess the ability to utilize sulfa drugs metabolically, producing alternate products that presumably inhibit downstream enzymes requiring the produced dihydropteroate. Recent work has established an off-target effect of sulfonamide antibiotics on a eukaryotic enzyme, sepiapterin reductase, causing alterations in neurotransmitter synthesis. Given that inhibitors of both DHFR and DHPS are designed to mimic their cognate substrate, which contain shared substructures, it is reasonable to expect such \u201coff-target\u201d effects. These inhibitors are also likely to interact with the enzymatic neighbors in the folate pathway that bind products of the DHFR or DHPS enzymes and\/or substrates of similar substructure. Computational studies designed to assess polypharmacology reiterate these conclusions. This leads to hypotheses exploring the vast utility of multiple members of the folate pathway for modulating cellular metabolism, and includes an appealing capacity for prokaryotic-specific polypharmacology for antimicrobial applications.<\/jats:p>","DOI":"10.3390\/antibiotics3010001","type":"journal-article","created":{"date-parts":[[2014,1,21]],"date-time":"2014-01-21T11:55:07Z","timestamp":1390305307000},"page":"1-28","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":95,"title":["Utility of the Biosynthetic Folate Pathway for Targets in Antimicrobial Discovery"],"prefix":"10.3390","volume":"3","author":[{"given":"Christina","family":"Bourne","sequence":"first","affiliation":[{"name":"Department of Veterinary Pathobiology, Oklahoma State University, 250 McElroy Hall, Stillwater,  OK 74078, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2014,1,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1038\/sj.bjp.0707432","article-title":"Novel approaches to developing new antibiotics for bacterial infections","volume":"152","author":"Coates","year":"2007","journal-title":"Br. J. Pharmacol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1126\/science.1176667","article-title":"Antibiotics for emerging pathogens","volume":"325","author":"Fischbach","year":"2009","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1016\/j.bcp.2005.11.025","article-title":"When will the genomics investment pay off for antibacterial discovery?","volume":"71","author":"Mills","year":"2006","journal-title":"Biochem. Pharmacol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1038\/nrd2201","article-title":"Drugs for bad bugs: Confronting the challenges of antibacterial discovery","volume":"6","author":"Payne","year":"2007","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1086\/595011","article-title":"Bad bugs, no drugs: No ESKAPE! An update from the Infectious Diseases Society of America","volume":"48","author":"Boucher","year":"2009","journal-title":"Clin. Infect. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1038\/nm0610-628","article-title":"Up against the wall","volume":"16","author":"Torres","year":"2010","journal-title":"Nat. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1128\/CMR.00030-10","article-title":"Challenges of antibacterial discovery","volume":"24","author":"Silver","year":"2011","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1038\/nrd2961","article-title":"Lessons from 60 years of pharmaceutical innovation","volume":"8","author":"Munos","year":"2009","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1038\/nrd2132","article-title":"Drugs, their targets and the nature and number of drug targets","volume":"5","author":"Imming","year":"2006","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1002\/cmdc.200800411","article-title":"Pharmacological promiscuity: Dependence on compound properties and target specificity in a set of recent Roche compounds","volume":"4","author":"Peters","year":"2009","journal-title":"ChemMedChem"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1038\/nchembio.118","article-title":"Network pharmacology: The next paradigm in drug discovery","volume":"4","author":"Hopkins","year":"2008","journal-title":"Nat. Chem. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.sbi.2006.01.013","article-title":"Can we rationally design promiscuous drugs?","volume":"16","author":"Hopkins","year":"2006","journal-title":"Curr. Opin. Struct. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1038\/nrd3267","article-title":"The antibiotics market","volume":"9","author":"Hamad","year":"2010","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1139\/O08-011","article-title":"Small and lethal: Searching for new antibacterial compounds with novel modes of action","volume":"86","author":"Pathania","year":"2008","journal-title":"Biochem. Cell. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.1073\/pnas.0909181107","article-title":"Blueprint for antimicrobial hit discovery targeting metabolic networks","volume":"107","author":"Shen","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1021\/jm9014229","article-title":"Systematic analysis of public domain compound potency data identifies selective molecular scaffolds across druggable target families","volume":"53","author":"Hu","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1038\/nature08506","article-title":"Predicting new molecular targets for known drugs","volume":"462","author":"Keiser","year":"2009","journal-title":"Nature"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1093\/bib\/bbr028","article-title":"Mining small-molecule screens to repurpose drugs","volume":"12","author":"Swamidass","year":"2011","journal-title":"Brief. Bioinform."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1098\/rstb.2007.2044","article-title":"Antibiotics as signalling molecules","volume":"362","author":"Yim","year":"2007","journal-title":"Philos. Trans. R. Soc. Lond. B Biol. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1126\/science.1155157","article-title":"Bacteria subsisting on antibiotics","volume":"320","author":"Dantas","year":"2008","journal-title":"Science"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4176","DOI":"10.1073\/pnas.1018301108","article-title":"Depletion of antibiotic targets has widely varying effects on growth","volume":"108","author":"Wei","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e1000474","DOI":"10.1371\/journal.pcbi.1000474","article-title":"A mapping of drug space from the viewpoint of small molecule metabolism","volume":"5","author":"Adams","year":"2009","journal-title":"PLoS Comput. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e1000976","DOI":"10.1371\/journal.pcbi.1000976","article-title":"The Mycobacterium tuberculosis drugome and its polypharmacological implications","volume":"6","author":"Kinnings","year":"2010","journal-title":"PLoS Comput. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Maggiora, G.M. (2011). Is there a future for computational chemistry in drug research?. J. Comput. Aided Mol. Des.","DOI":"10.1007\/s10822-011-9493-2"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1038\/nchembio.739","article-title":"Microbial metabolic exchange\u2014The chemotype-to-phenotype link","volume":"8","author":"Phelan","year":"2012","journal-title":"Nat. Chem. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"10267","DOI":"10.1021\/bi101540g","article-title":"The chemical basis of pharmacology","volume":"49","author":"Keiser","year":"2010","journal-title":"Biochemistry"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1002\/bies.10114","article-title":"The folic acid biosynthesis pathway in bacteria: Evaluation of potential for antibacterial drug discovery","volume":"24","author":"Bermingham","year":"2002","journal-title":"Bioessays"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1080\/08893110701337727","article-title":"Structural characteristics of antifolate dihydrofolate reductase enzyme interactions","volume":"12","author":"Cody","year":"2006","journal-title":"Crystallogr. Rev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"31","DOI":"10.2174\/138945007779315524","article-title":"Targeting purine and pyrimidine metabolism in human apicomplexan parasites","volume":"8","author":"Hyde","year":"2007","journal-title":"Curr. Drug Targets"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1431","DOI":"10.1104\/pp.016915","article-title":"One-carbon metabolism in plants. Regulation of tetrahydrofolate synthesis during germination and seedling development","volume":"131","author":"Jabrin","year":"2003","journal-title":"Plant. Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1016\/j.drudis.2006.08.003","article-title":"Inhibitors of de novo folate enzymes in Plasmodium falciparum","volume":"11","author":"Nzila","year":"2006","journal-title":"Drug Discov. Today"},{"key":"ref_32","first-page":"e203","article-title":"Acquired antibiotic resistance genes: An overview","volume":"2","author":"Mevius","year":"2011","journal-title":"Front. Microbiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.drup.2009.02.001","article-title":"Mutational \u201chot-spots\u2019\u201d in mammalian, bacterial and protozoal dihydrofolate reductases associated with antifolate resistance: Sequence and structural comparison","volume":"12","author":"Volpato","year":"2009","journal-title":"Drug Resist. Updat."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1517\/13543776.2011.587804","article-title":"Antifolate agents: A patent review (2006\u20132010)","volume":"21","author":"Wright","year":"2011","journal-title":"Expert Opin. Ther. Pat."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1038\/nbt1284","article-title":"Relating protein pharmacology by ligand chemistry","volume":"25","author":"Keiser","year":"2007","journal-title":"Nat. Biotechnol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.chembiol.2011.12.012","article-title":"Systems biology and systems chemistry: New directions for drug discovery","volume":"19","author":"Brown","year":"2012","journal-title":"Chem. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1038\/nbt1228","article-title":"Global mapping of pharmacological space","volume":"24","author":"Paolini","year":"2006","journal-title":"Nat. Biotechnol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1038\/nchembio0705-64","article-title":"Small molecules: The missing link in the central dogma","volume":"1","author":"Schreiber","year":"2005","journal-title":"Nat. Chem. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"6681","DOI":"10.1021\/jm049504o","article-title":"Virtual screening of human 5-aminoimidazole-4-carboxamide ribonucleotide transformylase against the NCI diversity set by use of AutoDock to identify novel nonfolate inhibitors","volume":"47","author":"Li","year":"2004","journal-title":"J. Med. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1042\/bj2820197","article-title":"Inhibition of folate-dependent enzymes by non-steroidal anti-inflammatory drugs","volume":"282","author":"Baggott","year":"1992","journal-title":"Biochem. J."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"18034","DOI":"10.1074\/jbc.M313691200","article-title":"Crystal structures of human bifunctional enzyme aminoimidazole-4-carboxamide ribonucleotide transformylase\/IMP cyclohydrolase in complex with potent sulfonyl-containing antifolates","volume":"279","author":"Cheong","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1705","DOI":"10.1016\/j.str.2004.07.011","article-title":"Crystal structure of 7,8-dihydropteroate synthase from Bacillus anthracis; Mechanism and novel inhibitor design","volume":"12","author":"Babaoglu","year":"2004","journal-title":"Structure"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1364","DOI":"10.1021\/jm0004493","article-title":"Bisubstrate analogue inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase: Synthesis and biochemical and crystallographic studies","volume":"44","author":"Shi","year":"2001","journal-title":"J. Med. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4303","DOI":"10.1016\/j.bmc.2012.05.060","article-title":"Bisubstrate analog inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase: New lead exhibits a distinct binding mode","volume":"20","author":"Shi","year":"2012","journal-title":"Bioorg. Med. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.jsb.2009.01.001","article-title":"X-ray structure of the ternary MTX-NADPH complex of the anthrax dihydrofolate reductase: A pharmacophore for dual-site inhibitor design","volume":"166","author":"Bennett","year":"2009","journal-title":"J. Struct. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e14165","DOI":"10.1371\/journal.pone.0014165","article-title":"Crystal structure of the 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase*dihydropteroate synthase bifunctional enzyme from Francisella tularensis","volume":"5","author":"Pemble","year":"2010","journal-title":"PLoS One"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"377","DOI":"10.2174\/092986706775527938","article-title":"Towards species-specific antifolates","volume":"13","author":"Chan","year":"2006","journal-title":"Curr. Med. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"e245","DOI":"10.1186\/1471-2164-8-245","article-title":"Comparative genomics of bacterial and plant folate synthesis and salvage: Predictions and validations","volume":"8","author":"Noiriel","year":"2007","journal-title":"BMC Genomics"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1111\/j.1365-2958.2004.04339.x","article-title":"An alternative pathway for reduced folate biosynthesis in bacteria and halophilic archaea","volume":"54","author":"Levin","year":"2004","journal-title":"Mol. Microbiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1080\/08893110701337800","article-title":"Structural characteristics of small-molecule antifolate compounds","volume":"12","author":"Schwalbe","year":"2006","journal-title":"Crystallogr. Rev."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"12","DOI":"10.2174\/1874940200801010012","article-title":"Folate biosynthesis-Reappraisal of old and novel targets in the search for new antimicrobials","volume":"1","author":"Swarbrick","year":"2008","journal-title":"Open Enzyme Inhib. J."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1093\/nar\/28.1.235","article-title":"The protein data bank","volume":"28","author":"Berman","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1107\/S0907444908012262","article-title":"Structures of Mycobacterium tuberculosis folylpolyglutamate synthase complexed with ADP and AMPPCP","volume":"D64","author":"Young","year":"2008","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1126\/science.1232972","article-title":"Tetrahydrobiopterin biosynthesis as an off-target of sulfa drugs","volume":"340","author":"Haruki","year":"2013","journal-title":"Science"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"10062","DOI":"10.1074\/jbc.270.17.10062","article-title":"Characterization of mouse and human GTP cyclohydrolase I genes. Mutations in patients with GTP cyclohydrolase I deficiency","volume":"270","author":"Ichinose","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1093\/jb\/mvi120","article-title":"Novel reaction mechanism of GTP cyclohydrolase I. High-resolution X-ray crystallography of Thermus thermophilus HB8 enzyme complexed with a transition state analogue, the 8-oxoguanine derivative","volume":"138","author":"Tanaka","year":"2005","journal-title":"J. Biochem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"e33481","DOI":"10.1371\/journal.pone.0033481","article-title":"Structures of Helicobacter pylori shikimate kinase reveal a selective inhibitor-induced-fit mechanism","volume":"7","author":"Cheng","year":"2012","journal-title":"PLoS One"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"423","DOI":"10.2174\/138945007780059004","article-title":"Mycobacterial shikimate pathway enzymes as targets for drug design","volume":"8","author":"Ducati","year":"2007","journal-title":"Curr. Drug Targets"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"13010","DOI":"10.1073\/pnas.0603638103","article-title":"Molecular basis for the herbicide resistance of Roundup Ready crops","volume":"103","author":"Funke","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"e29","DOI":"10.1186\/2050-6511-14-29","article-title":"Comprehensive database of Chorismate synthase enzyme from shikimate pathway in pathogenic bacteria","volume":"14","author":"Pitchandi","year":"2013","journal-title":"BMC Pharmacol. Toxicol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1016\/j.ijbiomac.2011.07.011","article-title":"Structural analysis of chorismate synthase from Plasmodium falciparum: A novel target for antimalaria drug discovery","volume":"49","author":"Tapas","year":"2011","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1002\/bies.20420","article-title":"Mitochondrial one-carbon metabolism is adapted to the specific needs of yeast, plants and mammals","volume":"28","author":"Christensen","year":"2006","journal-title":"Bioessays"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1016\/S0022-2836(02)01303-7","article-title":"Biosynthesis of pteridines. Reaction mechanism of GTP cyclohydrolase I","volume":"326","author":"Rebelo","year":"2003","journal-title":"J. Mol. Biol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1016\/S0969-2126(01)00179-4","article-title":"Atomic structure of GTP cyclohydrolase I","volume":"3","author":"Nar","year":"1995","journal-title":"Structure"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1212","DOI":"10.1073\/pnas.022646999","article-title":"Crystal structure of the stimulatory complex of GTP cyclohydrolase I and its feedback regulatory protein GFRP","volume":"99","author":"Maita","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"13567","DOI":"10.1073\/pnas.240463497","article-title":"Zinc plays a key role in human and bacterial GTP cyclohydrolase I","volume":"97","author":"Auerbach","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"37586","DOI":"10.1074\/jbc.M607114200","article-title":"Discovery of a new prokaryotic type I GTP cyclohydrolase family","volume":"281","author":"Bonnett","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"6936","DOI":"10.1128\/JB.00287-09","article-title":"Zinc-independent folate biosynthesis: Genetic, biochemical, and structural investigations reveal new metal dependence for GTP cyclohydrolase IB","volume":"191","author":"Sankaran","year":"2009","journal-title":"J. Bacteriol."},{"key":"ref_69","unstructured":"Maltseva, N., Kim, Y., Kwon, K., Anderson, W.F., and Joachimiak, A. Crystal structure of GTP cyclohydrolase I from Yersinia pestis complexed with GTP. Available online:http:\/\/rcsb.org\/pdb\/explore\/explore.do?structureId=4DU6\/."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.1016\/j.str.2007.06.018","article-title":"Structure and function of the E. coli dihydroneopterin triphosphate pyrophosphatase: A Nudix enzyme involved in folate biosynthesis","volume":"15","author":"Gabelli","year":"2007","journal-title":"Structure"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.jmb.2007.02.009","article-title":"Structural basis for the aldolase and epimerase activities of Staphylococcus aureus dihydroneopterin aldolase","volume":"368","author":"Blaszczyk","year":"2007","journal-title":"J. Mol. Biol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.jmb.2005.03.023","article-title":"Regulation by oligomerization in a mycobacterial folate biosynthetic enzyme","volume":"349","author":"Goulding","year":"2005","journal-title":"J. Mol. Biol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"15232","DOI":"10.1021\/bi060949j","article-title":"Mechanism of dihydroneopterin aldolase: Functional roles of the conserved active site glutamate and lysine residues","volume":"45","author":"Wang","year":"2006","journal-title":"Biochemistry"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1016\/j.jmb.2006.05.038","article-title":"Crystal structure of the bifunctional dihydroneopterin aldolase\/6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase from Streptococcus pneumoniae","volume":"360","author":"Garcon","year":"2006","journal-title":"J. Mol. Biol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"2214","DOI":"10.1128\/jb.175.8.2214-2220.1993","article-title":"A bifunctional protein in the folate biosynthetic pathway of Streptococcus pneumoniae with dihydroneopterin aldolase and hydroxymethyldihydropterin pyrophosphokinase activities","volume":"175","author":"Lopez","year":"1993","journal-title":"J. Bacteriol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/0378-1119(95)00203-I","article-title":"Two domains with amino-acid sequence similarity are required for dihydroneopterin aldolase function in the multifunctional folic acid synthesis Fas protein of Pneumocystis carinii","volume":"160","author":"Volpe","year":"1995","journal-title":"Gene"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1709","DOI":"10.1021\/jm030497y","article-title":"Discovery of potent inhibitors of dihydroneopterin aldolase using CrystaLEAD high-throughput X-ray crystallographic screening and structure-directed lead optimization","volume":"47","author":"Sanders","year":"2004","journal-title":"J. Med. Chem."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1016\/j.jmb.2004.04.034","article-title":"Biosynthesis of tetrahydrofolate in plants: Crystal structure of 7,8-dihydroneopterin aldolase from Arabidopsis thaliana reveals a novel adolase class","volume":"339","author":"Bauer","year":"2004","journal-title":"J. Mol. Biol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"4158","DOI":"10.1128\/JB.00416-09","article-title":"6-pyruvoyltetrahydropterin synthase paralogs replace the folate synthesis enzyme dihydroneopterin aldolase in diverse bacteria","volume":"191","author":"Pribat","year":"2009","journal-title":"J. Bacteriol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1111\/j.1365-2958.2007.06073.x","article-title":"An atypical orthologue of 6-pyruvoyltetrahydropterin synthase can provide the missing link in the folate biosynthesis pathway of malaria parasites","volume":"67","author":"Dittrich","year":"2008","journal-title":"Mol. Microbiol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1016\/j.pt.2008.08.004","article-title":"Plasmodium falciparum: A paradigm for alternative folate biosynthesis in diverse microorganisms?","volume":"24","author":"Hyde","year":"2008","journal-title":"Trends Parasitol."},{"key":"ref_82","first-page":"193","article-title":"Crystallization and preliminary X-ray crystallographic characterization of TrmFO, a folate-dependent tRNA methyltransferase from Thermotoga maritima","volume":"64","author":"Cicmil","year":"2008","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/S0083-6729(08)00415-9","article-title":"The structure and mechanism of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase","volume":"79","author":"Derrick","year":"2008","journal-title":"Vitam. Horm."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.bmc.2011.11.032","article-title":"Bisubstrate analogue inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase: New design with improved properties","volume":"20","author":"Shi","year":"2012","journal-title":"Bioorg. Med. Chem."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/S0014-5793(99)00860-1","article-title":"A X-ray structure of the ternary complex of 7,8-dihydro-6-hydroxymethylpterinpyrophosphokinase from Escherichia coli with ATP and a substrate analogue","volume":"456","author":"Stammers","year":"1999","journal-title":"FEBS Lett."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"e59535","DOI":"10.1371\/journal.pone.0059535","article-title":"Exploring the chemical space around 8-mercaptoguanine as a route to new inhibitors of the folate biosynthesis enzyme HPPK","volume":"8","author":"Chhabra","year":"2013","journal-title":"PLoS One"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"e29444","DOI":"10.1371\/journal.pone.0029444","article-title":"Structure of S. aureus HPPK and the discovery of a new substrate site inhibitor","volume":"7","author":"Chhabra","year":"2012","journal-title":"PLoS One"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1042\/bj20031850","article-title":"Kinetic and structural characterization of a product complex of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase from Escherichia coli","volume":"380","author":"Garcon","year":"2004","journal-title":"Biochem. J."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"40274","DOI":"10.1074\/jbc.M103837200","article-title":"Unusual conformational changes in 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase as revealed by X-ray crystallography and NMR","volume":"276","author":"Xiao","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/S0969-2126(99)80065-3","article-title":"Crystal structure of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase, a potential target for the development of novel antimicrobial agents","volume":"7","author":"Xiao","year":"1999","journal-title":"Structure"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1107\/S0907444907047452","article-title":"Structure and activity of Yersinia pestis 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase as a novel target for the development of antiplague therapeutics","volume":"63","author":"Blaszczyk","year":"2007","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1016\/j.str.2004.02.003","article-title":"Reaction trajectory of pyrophosphoryl transfer catalyzed by 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase","volume":"12","author":"Blaszczyk","year":"2004","journal-title":"Structure"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.1021\/bi036053l","article-title":"Essential roles of a dynamic loop in the catalysis of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase","volume":"43","author":"Blaszczyk","year":"2004","journal-title":"Biochemistry"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1016\/S0969-2126(00)00502-5","article-title":"Catalytic center assembly of HPPK as revealed by the crystal structure of a ternary complex at 1.25 A resolution","volume":"8","author":"Blaszczyk","year":"2000","journal-title":"Structure"},{"key":"ref_95","unstructured":"Chhabra, S., Peat, T.S., and Swarbrick, J. Synthesis and SAR study of guanine based analogues for HPPK inhibitors. Available online:http:\/\/www.rcsb.org\/pdb\/explore\/explore.do?pdbId=4ad6\/."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1021\/jm900861d","article-title":"Structural studies of pterin-based inhibitors of dihydropteroate synthase","volume":"53","author":"Hevener","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1016\/j.jmb.2005.03.021","article-title":"The three-dimensional structure of the bifunctional 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase\/dihydropteroate synthase of Saccharomyces cerevisiae","volume":"348","author":"Lawrence","year":"2005","journal-title":"J. Mol. Biol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"e21","DOI":"10.1186\/1472-6807-11-21","article-title":"Crystal structures of Burkholderia cenocepacia dihydropteroate synthase in the apo-form and complexed with the product 7,8-dihydropteroate","volume":"11","author":"Morgan","year":"2011","journal-title":"BMC Struct. Biol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1042\/BJ20071598","article-title":"Dihydropteroate synthase from Streptococcus pneumoniae: Structure, ligand recognition and mechanism of sulfonamide resistance","volume":"412","author":"Levy","year":"2008","journal-title":"Biochem. J."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1006\/jmbi.1997.0944","article-title":"Structure and function of the dihydropteroate synthase from Staphylococcus aureus","volume":"268","author":"Hampele","year":"1997","journal-title":"J. Mol. Biol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1110","DOI":"10.1126\/science.1214641","article-title":"Catalysis and sulfa drug resistance in dihydropteroate synthase","volume":"335","author":"Yun","year":"2012","journal-title":"Science"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"10337","DOI":"10.1016\/S0021-9258(19)86714-5","article-title":"The characteristics and significance of sulfonamides as substrates for Escherichia coli dihydropteroate synthase","volume":"254","author":"Roland","year":"1979","journal-title":"J. Biol. Chem."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1002\/jhet.5570230265","article-title":"A galactoside derivative of a nitrosoisocytosine inhibitor of dihydropteroate synthase: Synthesis and biological evaluation","volume":"23","author":"Lever","year":"1986","journal-title":"J. Heterocycl. Chem."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1089\/mdr.2006.9992","article-title":"Genetic basis for sulfonamide resistance in Bacillus anthracis","volume":"13","author":"Valderas","year":"2007","journal-title":"Microb. Drug Resist."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1126\/science.1228980","article-title":"Para-aminosalicylic acid acts as an alternative substrate of folate metabolism in Mycobacterium tuberculosis","volume":"339","author":"Chakraborty","year":"2013","journal-title":"Science"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"4433","DOI":"10.1016\/j.bmc.2006.02.035","article-title":"Elucidation of sulfadoxine resistance with structural models of the bifunctional Plasmodium falciparum dihydropterin pyrophosphokinase-dihydropteroate synthase","volume":"14","author":"Louw","year":"2006","journal-title":"Bioorg. Med. Chem."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.1006\/jmbi.2000.4094","article-title":"Crystal structure of Mycobacterium tuberculosis 7,8-dihydropteroate synthase in complex with pterin monophosphate: New insight into the enzymatic mechanism and sulfa-drug action","volume":"302","author":"Baca","year":"2000","journal-title":"J. Mol. Biol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"18916","DOI":"10.1074\/jbc.M413799200","article-title":"Escherichia coli FolC structure reveals an unexpected dihydrofolate binding site providing an attractive target for anti-microbial therapy","volume":"280","author":"Mathieu","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/0031-9422(94)00615-Z","article-title":"Isolation of dihydrofolate and folylpolyglutamate synthetase activities from Neurospora","volume":"38","author":"McDonald","year":"1995","journal-title":"Phytochemistry"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"5663","DOI":"10.1016\/S0021-9258(19)70680-2","article-title":"Pteroylpoly(gamma-glutamate) synthesis by Corynebacterium species. Studies on the mechanism of folypoly(gamma-glutamate) synthetase","volume":"255","author":"Shane","year":"198","journal-title":"J. Biol. Chem."},{"key":"ref_111","first-page":"277","article-title":"Cloning and characterization of the Neisseria gonorrhoeae MS11 folC gene","volume":"250","author":"Fussenegger","year":"1996","journal-title":"Mol. Gen. Genet."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"5625","DOI":"10.1016\/S0021-9258(18)89069-X","article-title":"Folylpoly-gamma-glutamate synthetase-dihydrofolate synthetase. Cloning and high expression of the Escherichia coli folC gene and purification and properties of the gene product","volume":"260","author":"Bognar","year":"1985","journal-title":"J. Biol. Chem."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1006\/jmbi.2001.4815","article-title":"Folate-binding triggers the activation of folylpolyglutamate synthetase","volume":"310","author":"Sun","year":"2001","journal-title":"J. Mol. Biol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1107\/S0907444906009796","article-title":"Mutation of Gly51 to serine in the P-loop of Lactobacillus casei folylpolyglutamate synthetase abolishes activity by altering the conformation of two adjacent loops","volume":"62","author":"Smith","year":"2006","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"2388","DOI":"10.1021\/bi701670y","article-title":"Mutagenesis of folylpolyglutamate synthetase indicates that dihydropteroate and tetrahydrofolate bind to the same site","volume":"47","author":"Sheng","year":"2008","journal-title":"Biochemistry"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.molbiopara.2010.03.012","article-title":"Characterisation of the bifunctional dihydrofolate synthase-folylpolyglutamate synthase from Plasmodium falciparum; a potential novel target for antimalarial antifolate inhibition","volume":"172","author":"Wang","year":"2010","journal-title":"Mol. Biochem. Parasitol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1038\/nchembio.108","article-title":"A domino effect in antifolate drug action in Escherichia coli","volume":"4","author":"Kwon","year":"2008","journal-title":"Nat. Chem. Biol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"9062","DOI":"10.1021\/bi00425a027","article-title":"Dihydrofolate synthetase and folylpolyglutamate synthetase: Direct evidence for intervention of acyl phosphate intermediates","volume":"27","author":"Banerjee","year":"1988","journal-title":"Biochemistry"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"3263","DOI":"10.1021\/bi00465a018","article-title":"Crystal structures of Escherichia coli dihydrofolate reductase: The NADP+ holoenzyme and the folate .cntdot. NADP+ ternary complex. Substrate binding and a model for the transition state","volume":"29","author":"Bystroff","year":"1990","journal-title":"Biochemistry"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1021\/bi962337c","article-title":"Loop and subdomain movements in the mechanism of Escherichia coli dihydrofolate reductase: Crystallographic evidence","volume":"36","author":"Sawaya","year":"1997","journal-title":"Biochemistry"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"3556","DOI":"10.1021\/bi9924563","article-title":"Structural studies on bioactive compounds. 30. Crystal structure and molecular modeling studies on the Pneumocystis carinii dihydrofolate reductase cofactor complex with TAB, a highly selective antifolate","volume":"39","author":"Cody","year":"2000","journal-title":"Biochemistry"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"10159","DOI":"10.1073\/pnas.1307130110","article-title":"Functional significance of evolving protein sequence in dihydrofolate reductase from bacteria to humans","volume":"110","author":"Liu","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1016\/S0021-9258(19)75842-6","article-title":"The effects on 4-aminoantifolates on 5-formyltetrahydrofolate metabolism in L1210 cells. A biochemical basis of the selectivity of leucovorin rescue","volume":"262","author":"Matherly","year":"1987","journal-title":"J. Biol. Chem."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1128\/AAC.28.3.446","article-title":"Reversal of the in vitro susceptibility of enterococci to trimethoprim-sulfamethoxazole by folinic acid","volume":"28","author":"Zervos","year":"1985","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"5057","DOI":"10.1074\/jbc.270.10.5057","article-title":"Methotrexate-resistant variants of human dihydrofolate reductase with substitutions of leucine 22. Kinetics, crystallography, and potential as selectable markers","volume":"270","author":"Lewis","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"2837","DOI":"10.1093\/jac\/dks321","article-title":"Molecular mechanisms of higher MICs of antibiotics and quaternary ammonium compounds for Escherichia coli isolated from bacteraemia","volume":"67","year":"2012","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"5406","DOI":"10.1128\/AAC.00580-10","article-title":"LmrS is a multidrug efflux pump of the major facilitator superfamily from Staphylococcus aureus","volume":"54","author":"Floyd","year":"2010","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"2288","DOI":"10.1128\/AAC.40.10.2288","article-title":"Multidrug efflux in intrinsic resistance to trimethoprim and sulfamethoxazole in Pseudomonas aeruginosa","volume":"40","author":"Kohler","year":"1996","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1093\/jac\/dkq079","article-title":"Natural and synthetic compounds such as trimethoprim behave as inhibitors of efflux in Gram-negative bacteria","volume":"65","author":"Piddock","year":"2010","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"4303","DOI":"10.1021\/bi982728m","article-title":"Ligand-induced conformational changes in the crystal structures of Pneumocystis carinii dihydrofolate reductase complexes with folate and NADP+","volume":"38","author":"Cody","year":"1999","journal-title":"Biochemistry"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1107\/S0907444910041004","article-title":"Structural analysis of Pneumocystis carinii and human DHFR complexes with NADPH and a series of five potent 6-[5'-(omega-carboxyalkoxy)benzyl]pyrido[2,3-d]pyrimidine derivatives","volume":"67","author":"Cody","year":"2011","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"2669","DOI":"10.1128\/AAC.00172-13","article-title":"Kinetic and structural analysis for potent antifolate inhibition of Pneumocystis jirovecii, Pneumocystis carinii, and human dihydrofolate reductases and their active-site variants","volume":"57","author":"Cody","year":"2013","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"2447","DOI":"10.1021\/jm990079m","article-title":"Pneumocystis carinii and Toxoplasma gondii dihydrofolate reductase inhibitors and antitumor agents: Synthesis and biological activities of 2,4-diamino-5-methyl-6-[(monosubstituted anilino) methyl]-pyrido [2,3-d] pyrimidines","volume":"42","author":"Gangjee","year":"1999","journal-title":"J. Med. Chem."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1021\/jm010407u","article-title":"Inhibition of Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium dihydrofolate reductases by 2,4-diamino-5-[2-methoxy-5-(omega-carboxyalkyloxy)benzyl]pyrimidines: Marked improvement in potency relative to trimethoprim and species selectivity relative to piritrexim","volume":"45","author":"Rosowsky","year":"2002","journal-title":"J. Med. Chem."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1136\/jcp.21.2.202","article-title":"Trimethoprim: Laboratory and clinical studies","volume":"21","author":"Darrell","year":"1968","journal-title":"J. Clin. Pathol."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"131","DOI":"10.2217\/17460913.4.2.131","article-title":"Iclaprim: A novel dihydrofolate reductase inhibitor for skin and soft tissue infections","volume":"4","author":"Morgan","year":"2009","journal-title":"Future Microbiol."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"4217","DOI":"10.1016\/j.bmcl.2003.07.023","article-title":"Iclaprim, a novel diaminopyrimidine with potent activity on trimethoprim sensitive and resistant bacteria","volume":"13","author":"Schneider","year":"2003","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1093\/jac\/dkp024","article-title":"Increased hydrophobic interactions of iclaprim with Staphylococcus aureus dihydrofolate reductase are responsible for the increase in affinity and antibacterial activity","volume":"63","author":"Oefner","year":"2009","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"15962","DOI":"10.1021\/bi9915263","article-title":"Characterization of rates of ring-flipping in trimethoprim in its ternary complexes with Lactobacillus casei dihydrofolate reductase and coenzyme analogues","volume":"38","author":"Polshakov","year":"1999","journal-title":"Biochemistry"},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1128\/AAC.45.4.1104-1108.2001","article-title":"Multiple mutations modulate the function of dihydrofolate reductase in trimethoprim-resistant Streptococcus pneumoniae","volume":"45","author":"Maskell","year":"2001","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1093\/jac\/48.6.935","article-title":"Resistance to trimethoprim-sulfamethoxazole and modifications in genes coding for dihydrofolate reductase and dihydropteroate synthase in European Streptococcus pneumoniae isolates","volume":"48","author":"Schmitz","year":"2001","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1051\/vetres:2001123","article-title":"Resistance to trimethoprim and sulfonamides","volume":"32","author":"Skold","year":"2001","journal-title":"Vet. Res."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"4643","DOI":"10.1128\/AAC.48.12.4643-4649.2004","article-title":"Functional cloning of Bacillus anthracis DHFR and confirmation of natural resistance to trimethoprim","volume":"48","author":"Barrow","year":"2004","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"S3","DOI":"10.1016\/j.amjmed.2006.03.011","article-title":"Mechanisms of antimicrobial resistance in bacteria","volume":"119","author":"Tenover","year":"2006","journal-title":"Am. J. Med."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"7327","DOI":"10.1021\/jm100727t","article-title":"Targeted mutations of Bacillus anthracis dihydrofolate reductase condense complex structure-activity relationships","volume":"53","author":"Beierlein","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"3825","DOI":"10.1128\/AAC.00361-10","article-title":"Inhibition of antibiotic-resistant Staphylococcus aureus by the broad-spectrum dihydrofolate reductase inhibitor RAB1","volume":"54","author":"Bourne","year":"2010","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.jsb.2009.12.011","article-title":"Towards the understanding of resistance mechanisms in clinically isolated trimethoprim-resistant, methicillin-resistant Staphylococcus aureus dihydrofolate reductase","volume":"170","author":"Frey","year":"2010","journal-title":"J. Struct. Biol."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.bbapap.2012.09.001","article-title":"Structure-activity relationship for enantiomers of potent inhibitors of B. anthracis dihydrofolate reductase","volume":"1834","author":"Bourne","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1080\/1120009X.1993.11741084","article-title":"Structure-activity relationships of dihydrofolate reductase inhibitors","volume":"5","author":"Bowden","year":"1993","journal-title":"J. Chemother."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"1298","DOI":"10.1016\/j.jmb.2009.02.045","article-title":"Crystal structures of wild-type and mutant methicillin-resistant Staphylococcus aureus dihydrofolate reductase reveal an alternate conformation of NADPH that may be linked to trimethoprim resistance","volume":"387","author":"Frey","year":"2009","journal-title":"J. Mol. Biol."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"4366","DOI":"10.1016\/j.bmcl.2006.05.047","article-title":"Analysis of compleses of inhibitors with Cryptosporidium hominis DHFR leads to a new trimethoprim derivative","volume":"16","author":"Popov","year":"2006","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1038\/nature10388","article-title":"Antibiotic resistance is ancient","volume":"477","author":"King","year":"2011","journal-title":"Nature"},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"e34953","DOI":"10.1371\/journal.pone.0034953","article-title":"Antibiotic resistance is prevalent in an isolated cave microbiome","volume":"7","author":"Bhullar","year":"2012","journal-title":"PLoS One"}],"container-title":["Antibiotics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-6382\/3\/1\/1\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:07:33Z","timestamp":1760216853000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-6382\/3\/1\/1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,1,21]]},"references-count":153,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2014,3]]}},"alternative-id":["antibiotics3010001"],"URL":"https:\/\/doi.org\/10.3390\/antibiotics3010001","relation":{},"ISSN":["2079-6382"],"issn-type":[{"value":"2079-6382","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,1,21]]}}}