Skip to main content
SpringerLink
Log in

The Antifolates

  • Chapter
  • First Online:
Antibacterials

Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 26))

Abstract

Cells rely on the synthesis of essential metabolites to ensure proper cell function, growth, and survival. Folate biosynthesis is a ubiquitous pathway found in organisms and is responsible for the generation of thymidine, methionine, histidine, and purines. Drugs that target essential enzymes along this pathway have been known since the 1930s as having clinical utility as antibacterial, anticancer, antimalarial, and antifungal agents. These drugs are commonly referred to as antifolates. However, bacterial resistance mechanisms against the antibacterial antifolates have emerged that have rendered many of these antifolates as unsuitable treatment options, and threaten those antifolates that are still used today. Here we describe the history of the drugs that target the essential enzymes in folate biosynthesis, the bacterial resistance mechanisms that have emerged to limit their use, and the current strategies that are being employed to overcome the prevalent resistance mechanisms.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Institutional subscriptions

References

  1. Domagk G (1935) Ein Beitrag zur Chemotherapie der bakteriellen Infektionen. Dtsch Med Wochenschr 61:250–253. doi:10.1055/s-0028-1129486

    Article  CAS  Google Scholar 

  2. Gerhard D (1942) Die Sulfonamidtherapie bakterieller Infektionen. Hoppe-Seyler’s Zeitschrift für Physiol Chemie 274:55. doi:10.1515/bchm2.1942.274.1-6.55

    Article  Google Scholar 

  3. Trefouel J, Trefouel MJ, Nitti F, Bovet D (1937) Mode of action of p-aminophenylsulfonamide and its nitrogen derivatives in experimental streptococcus septicemias. Press Medicale 45:839–840

    CAS  Google Scholar 

  4. Roland S, Ferone R, Harvey RJ, Styles VL, Morrison RW (1979) The characteristics and significance of sulfonamides as substrates for Escherichia coli dihydropteroate synthase. J Biol Chem 254:10337–10345

    PubMed  CAS  Google Scholar 

  5. Achari A, Somers DO, Champness JN, Bryant PK, Rosemond J, Stammers DK (1997) Crystal structure of the anti-bacterial sulfonamide drug target dihydropteroate synthase. Nat Struct Biol 4:490–497. doi:10.1038/nsb0697-490

    Article  PubMed  CAS  Google Scholar 

  6. Then R, Angehrn P (1973) Sulphonamide-induced “thymineless death” in Escherichia coli. J Gen Microbiol 76:255–263. doi:10.1099/00221287-76-2-255

    Article  PubMed  CAS  Google Scholar 

  7. Rutman RJ, Cantarow A, Paschkis KE (1954) Studies in 2-acetylaminofluorene carcinogenesis. III. The utilization of uracil-2-C14 by preneoplastic rat liver and rat hepatoma. Cancer Res 14:119–123

    PubMed  CAS  Google Scholar 

  8. Heidelberger C, Chaudhuri NK, Danneberg P, Mooren D, Griesbach L, Duschinsky R, Schnitzer RJ, Pleven E, Scheiner J (1957) Fluorinated pyrimidines, a new class of tumour-inhibitory compounds. Nature 179:663–666. doi:10.1038/179663a0

    Article  PubMed  CAS  Google Scholar 

  9. Longley D, Harkin D, Johnston P (2003) 5-Fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer 3:330–338. doi:10.1038/nrc1074

    Article  PubMed  CAS  Google Scholar 

  10. Wohlhueter RM, McIvor RS, Plagemann PG (1980) Facilitated transport of uracil and 5-fluorouracil, and permeation of orotic acid into cultured mammalian cells. J Cell Physiol 104:309–319. doi:10.1002/jcp.1041040305

    Article  PubMed  CAS  Google Scholar 

  11. Jackman AL, Taylor GA, Gibson W, Kimbell R, Brown M, Calvert AH, Judson IR, Hughes LR (1991) ICI D1694, a quinazoline antifolate thymidylate synthase inhibitor that is a potent inhibitor of L1210 tumor cell growth in vitro and in vivo: a new agent for clinical study. Cancer Res 51:5579–5586

    PubMed  CAS  Google Scholar 

  12. Cunningham D, Cocconi G, Van Cutsem E, Francois E, Gustavsson B, Van Hazel G, Kerr D, Possinger K, Hietschold SM (1998) Open, randomized, multicenter trial of raltitrexed versus fluorouracil plus high-dose leucovorin in patients with advanced colorectal cancer. Tomudex Colorectal Cancer Study Group. J Clin Oncol 16:2943–2952

    Article  PubMed  Google Scholar 

  13. Taylor EC, Kuhnt D, Shih C, Rinzel SM, Grindey GB, Barredo J, Jannatipour M, Moran RG (1992) A dideazatetrahydrofolate analogue lacking a chiral center at C-6, N-[4- [2-(2-amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]- L-glutamic acid, is an inhibitor of thymidylate synthase. J Med Chem 35:4450–4454. doi:10.1021/jm00101a023

    Article  PubMed  CAS  Google Scholar 

  14. Hammoudeh DI, Daté M, Yun MK, Zhang W, Boyd VA, Viacava Follis A, Griffith E, Lee RE, Bashford D, White SW (2014) Identification and characterization of an allosteric inhibitory site on dihydropteroate synthase. ACS Chem Biol 9:1294–1302. doi:10.1021/cb500038g

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Myllykallio H, Lipowski G, Leduc D, Filee J, Forterre P, Liebl U (2002) An alternative flavin-dependent mechanism for thymidylate synthesis. Science 297:105–107. doi:10.1126/science.1072113

    Article  PubMed  CAS  Google Scholar 

  16. Dynes JL, Firtel RA (1989) Molecular complementation of a genetic marker in Dictyostelium using a genomic DNA library. Proc Natl Acad Sci U S A 86:7966–7970. doi:10.1073/pnas.86.20.7966

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Mishanina TV, Yu L, Karunaratne K, Mondal D, Corcoran JM, Choi MA, Kohen A (2016) An unprecedented mechanism of nucleotide methylation in organisms containing thyX. Science 351:507–510. doi:10.1126/science.aad0300

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Choi M, Karunaratne K, Kohen A (2016) Flavin-dependent thymidylate synthase as a new antibiotic target. Molecules 21:654. doi:10.3390/molecules21050654

    Article  CAS  Google Scholar 

  19. Koehn EM, Perissinotti LL, Moghram S, Prabhakar A, Lesley SA, Mathews II, Kohen A (2012) Folate binding site of flavin-dependent thymidylate synthase. Proc Natl Acad Sci 109:15722–15727. doi:10.1073/pnas.1206077109

    Article  PubMed  Google Scholar 

  20. Önen FE, Boum Y, Jacquement C, Spanedda MV, Jaber N, Scherman D, Myllykallio H, Herscovici J (2008) Design, synthesis and evaluation of potent thymidylate synthase X inhibitors. Bioorg Med Chem Lett 18:3628–3631. doi:10.1016/j.bmcl.2008.04.080

    Article  CAS  Google Scholar 

  21. Basta T, Boum Y, Briffotaux J, Becker HF, Lamarre-Jouenne I, Lambry J-C, Skouloubris S, Liebl U, Graille M, van Tilbeurgh H, Myllykallio H (2012) Mechanistic and structural basis for inhibition of thymidylate synthase ThyX. Open Biol 2:120120. doi:10.1098/rsob.120120

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Kögler M, Vanderhoydonck B, De Jonghe S, Rozenski J, Van Belle K, Herman J, Louat T, Parchina A, Sibley C, Lescrinier E, Herdewijn P (2011) Synthesis and evaluation of 5-substituted 2′-deoxyuridine monophosphate analogues as inhibitors of flavin-dependent thymidylate synthase in Mycobacterium tuberculosis. J Med Chem 54:4847–4862. doi:10.1021/jm2004688

    Article  PubMed  CAS  Google Scholar 

  23. Parchina A, Froeyen M, Margamuljana L, Rozenski J, DeJonghe S, Briers Y, Lavigne R, Herdewijn P, Lescrinier E (2013) Discovery of an acyclic nucleoside phosphonate that inhibits Mycobacterium tuberculosis ThyX based on the binding mode of a 5-Alkynyl substrate analogue. ChemMedChem 8:1373–1383. doi:10.1002/cmdc.201300146

    Article  PubMed  CAS  Google Scholar 

  24. McGuigan C, Derudas M, Gonczy B, Hinsinger K, Kandil S, Pertusati F, Serpi M, Snoeck R, Andrei G, Balzarini J, McHugh TD, Maitra A, Akorli E, Evangelopoulos D, Bhakta S (2014) ProTides of N-(3-(5-(2′-deoxyuridine))prop-2-ynyl)octanamide as potential anti-tubercular and anti-viral agents. Bioorg Med Chem 22:2816–2824. doi:10.1016/j.bmc.2014.02.056

    Article  PubMed  CAS  Google Scholar 

  25. Farber S, Diamond LK, Mercer RD, Sylvester RF, Wolff JA (1948) Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid (aminopterin). N Engl J Med 238:787–793. doi:10.1056/NEJM194806032382301

    Article  PubMed  CAS  Google Scholar 

  26. Goldin A, Venditti JM, Humphreys SR, Dennis D, Mantel N, Greenhouse SW (1955) A quantitative comparison of the antileukemic effectiveness of two folic acid antagonists in mice. J Natl Cancer Inst 15:1657–1664

    PubMed  CAS  Google Scholar 

  27. Chan ESL, Cronstein BN (2010) Methotrexate – how does it really work? Nat Rev Rheumatol 6:175–178. doi:10.1038/nrrheum.2010.5

    Article  PubMed  CAS  Google Scholar 

  28. Porcelli L, Assaraf YG, Azzariti A, Paradiso A, Jansen G, Peters GJ (2011) The impact of folate status on the efficacy of colorectal cancer treatment. Curr Drug Metab 12:975–984. doi:10.2174/138920011798062274

    Article  PubMed  CAS  Google Scholar 

  29. Assaraf YG (2007) Molecular basis of antifolate resistance. Cancer Metastasis Rev 26:153–181. doi:10.1007/s10555-007-9049-z

    Article  PubMed  CAS  Google Scholar 

  30. Falco EA, Goodwin LG, Hitchings GH, Rollo IM, Russell PB (1951) 2,4-Diaminopyrimidines–a new series of antimalarials. Br J Pharmacol Chemother 6:185–200. doi:10.1111/j.1476-5381.1951.tb00634.x

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Crowther AF, Levi AA (1953) Proguanil – the isolation of a metabolite with high antimalarial activity. Br J Pharmacol Chemother 8:93–97. doi:10.1111/j.1476-5381.1953.tb00758.x

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Hitchings GH, Elion GB, VanderWerff H, Falco EA (1948) Pyrimidine derivatives as antagonists of pteroylglutamic acid. J Biol Chem 174:765–766

    PubMed  CAS  Google Scholar 

  33. Roth B, Falco EA, Hitchings GH, Bushby SRM (1962) 5-Benzyl-2,4-diaminopyrimidines as antibacterial agents. I. Synthesis and antibacterial activity in vitro. J Med Pharm Chem 5:1103–1123. doi:10.1021/jm01241a004

    Article  CAS  Google Scholar 

  34. Fleming MP, Datta N, Grüneberg RN (1972) Trimethoprim resistance determined by R factors. Br Med J 1:726–728. doi:10.1136/bmj.1.5802.726

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Towner KJ, Slack RCB (1986) Effect of changing selection pressures on trimethoprim resistance in Enterobacteriaceae. Eur J Clin Microbiol 5:502–506. doi:10.1007/BF02017691

    Article  PubMed  CAS  Google Scholar 

  36. Amyes SGB, Towner KJ, Goldstein FW, Acar JF, Tait S, Young HK, Thomson CJ, Burdeska A, Then RL, Mee BJ (1990) Trimethoprim resistance; epidemiology and molecular aspects. J Med Microbiol 31:1–19

    Article  Google Scholar 

  37. Huovinen P, Sundstrom L, Swedberg G, Skold O (1995) Trimethoprim and sulfonamide resistance. Antimicrob Agents Chemother 39:279–289. doi:10.1128/AAC.39.2.279

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Then RL, Kohl I, Burdeska A (1992) Frequency and transferability of trimethoprim and sulfonamide resistance in methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis. J Chemother 4:67–71

    Article  CAS  PubMed  Google Scholar 

  39. Huang SH, Chen YC, Chuang YC, Chiu SK, Fung CP, Lu PL, Wang LS, Wu TL, Wang JT (2015) Prevalence of vancomycin-intermediate Staphylococcus aureus (VISA) and heterogeneous VISA among methicillin-resistant S. aureus with high vancomycin minimal inhibitory concentrations in Taiwan: a multicenter surveillance study, 2012-2013. J Microbiol Immunol Infect 49:701–707. doi:10.1016/j.jmii.2015.07.003

    Article  PubMed  CAS  Google Scholar 

  40. Fridkin SK, Hageman JC, Morrison M, Sanza LT, Como-Sabetti K, Jernigan JA, Harriman K, Harrison LH, Lynfield R, Farley MM (2005) Methicillin-resistant Staphylococcus aureus disease in three communities. N Engl J Med 352:1436–1444. doi:10.1056/NEJMoa043252

    Article  PubMed  CAS  Google Scholar 

  41. Naimi TS, LeDell KH, Como-Sabetti K, Borchardt SM, Boxrud DJ, Etienne J, Johnson SK, Vandenesch F, Fridkin S, O’Boyle C, Danila RN, Lynfield R (2003) Comparison of community- and health care-associated methicillin-resistant Staphylococcus aureus infection. JAMA 290:2976–2984

    Article  CAS  PubMed  Google Scholar 

  42. Dale GE, Broger C, D’Arcy A, Hartman PG, DeHoogt R, Jolidon S, Kompis I, Labhardt AM, Langen H, Locher H, Page MG, Stüber D, Then RL, Wipf B, Oefner C (1997) A single amino acid substitution in Staphylococcus aureus dihydrofolate reductase determines trimethoprim resistance. J Mol Biol 266:23–30. doi:10.1006/jmbi.1996.0770

    Article  PubMed  CAS  Google Scholar 

  43. Lyon BR, May JW, Skurray RA (1983) Analysis of plasmids in nosocomial strains of multiple-antibiotic-resistant Staphylococcus aureus. Antimicrob Agents Chemother 23:817–826. doi:10.1128/AAC.23.6.817

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Lyon BR, Tennent JM, May JW, Skurray RA (1986) Trimethoprim resistance encoded on a Staphylococcus aureus gentamicin resistance plasmid; cloning and transposon mutagenesis. FEMS Microbiol Lett 33:189–192. doi:10.1111/j.1574-6968.1986.tb01269.x

    Article  CAS  Google Scholar 

  45. Young HK, Skurray RA, Amyes SGB (1987) Plasmid-mediated trimethoprim-resistance in Staphylococcus aureus. Characterization of the first gram-positive plasmid dihydrofolate reductase (type S1). Biochem J 243:309–312. doi:10.1042/bj2430309

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Dale GE, Then RL, Stuber D (1993) Characterization of the gene for chromosomal trimethoprim-sensitive dihydrofolate reductase of Staphylococcus aureus ATCC 25923. Antimicrob Agents Chemother 37:1400–1405. doi:10.1128/AAC.37.7.1400.Updated

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Dale GE, Broger C, Hartman PG, Langen H, Page MGP, Then RL, Stuber D (1995) Characterization of the gene for the chromosomal dihydrofolate reductase (DHFR) of Staphylococcus epidermidis ATCC 14990: the origin of the trimethoprim-resistant S1 DHFR from Staphylococcus aureus? J Bacteriol 177:2965–2970

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Heaslet H, Harris M, Fahnoe K, Sarver R, Putz H, Chang J, Subramanyam C, Barreiro G, Miller JR (2009) Structural comparison of chromosomal and exogenous dihydrofolate reductase from Staphylococcus aureus in complex with the potent inhibitor trimethoprim. Proteins Struct Funct Bioinform 76:706–717. doi:10.1002/prot.22383

    Article  CAS  Google Scholar 

  49. Oefner C, Bandera M, Haldimann A, Laue H, Schulz H, Mukhija S, Parisi S, Weiss L, Lociuro S, Dale GE (2009) Increased hydrophobic interactions of iclaprim with Staphylococcus aureus dihydrofolate reductase are responsible for the increase in affinity and antibacterial activity. J Antimicrob Chemother 63:687–698. doi:10.1093/jac/dkp024

    Article  PubMed  CAS  Google Scholar 

  50. Sekiguchi J, Tharavichitkul P, Miyoshi-Akiyama T, Chupia V, Fujino T, Araake M, Irie A, Morita K, Kuratsuji T, Kirikae T (2005) Cloning and characterization of a novel trimethoprim-resistant dihydrofolate reductase from a nosocomial isolate of Staphylococcus aureus CM. S2 (IMCJ1454). Antimicrob Agents Chemother 49:3948–3951. doi:10.1128/AAC.49.9.3948

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Holden MTG, Lindsay JA, Corton C, Quail MA, Cockfield JD, Pathak S, Batra R, Parkhill J, Bentley SD, Edgeworth JD (2010) Genome sequence of a recently emerged, highly transmissible, multi-antibiotic- and antiseptic-resistant variant of methicillin-resistant Staphylococcus aureus, sequence type 239 (TW). J Bacteriol 192:888–892. doi:10.1128/JB.01255-09

    Article  PubMed  CAS  Google Scholar 

  52. Nurjadi D, Olalekan AO, Layer F, Shittu AO, Alabi A, Ghebremedhin B, Schaumburg F, Hofmann-Eifler J, Van Genderen PJJ, Caumes E, Fleck R, Mockenhaupt FP, Herrmann M, Kern WV, Abdulla S, Grobusch MP, Kremsner PG, Wolz C, Zanger P (2014) Emergence of trimethoprim resistance gene dfrG in Staphylococcus aureus causing human infection and colonization in sub-Saharan Africa and its import to Europe. J Antimicrob Chemother 69:2361–2368. doi:10.1093/jac/dku174

    Article  PubMed  CAS  Google Scholar 

  53. Kadlec K, Schwarz S (2009) Identification of a novel trimethoprim resistance gene, dfrK, in a methicillin-resistant Staphylococcus aureus ST398 strain and its physical linkage to the tetracycline resistance gene tet(L). Antimicrob Agents Chemother 53:776–778. doi:10.1128/AAC.01128-08

    Article  PubMed  CAS  Google Scholar 

  54. De Gopegui ER, Juan C, Zamorano L, Pérez JL, Oliver A (2012) Transferable multidrug resistance plasmid carrying cfr associated with tet(L), ant(4′)-Ia, and dfrK genes from a clinical methicillin-resistant Staphylococcus Aureus ST125 strain. Antimicrob Agents Chemother 56:2139–2142. doi:10.1128/AAC.06042-11

    Article  PubMed  CAS  Google Scholar 

  55. Amyes SGB, Smith JT (1974) R-factor trimethoprim resistance mechanism: an insusceptible target site. Biochem Biophys Res Commun 58:412–418. doi:10.1016/0006-291X(74)90380-5

    Article  PubMed  CAS  Google Scholar 

  56. Skold O, Widh A (1974) A new dihydrofolate reductase with low trimethoprim sensitivity induced by an R factor mediating high resistance to trimethoprim. J Biol Chem 249:4324–4325

    PubMed  CAS  Google Scholar 

  57. Young HK, Amyes SG (1986) A new mechanism of plasmid trimethoprim resistance. Characterization of an inducible dihydrofolate reductase. J Biol Chem 261:2503–2505

    PubMed  CAS  Google Scholar 

  58. Young H-K, Thomson CJ, Amyes SGB (1993) The induction of trimethoprim resistance encoded by the type IV dihydrofolate reductase gene. J Med Microbiol 38:256–261. doi:10.1099/00222615-38-4-256

    Article  PubMed  CAS  Google Scholar 

  59. White PA (2001) Current status of the aadA and dfr gene cassette families. J Antimicrob Chemother 47:495–496. doi:10.1093/jac/47.4.495

    Article  PubMed  CAS  Google Scholar 

  60. Kumar A, Chakraborti S, Joshi P, Chakrabarti P, Chakraborty R (2011) A multiple antibiotic and serum resistant oligotrophic strain, Klebsiella pneumoniae MB45 having novel dfrA30, is sensitive to ZnO QDs. Ann Clin Microbiol Antimicrob 10:19. doi:10.1186/1476-0711-10-19

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Blahna MT, Zalewski CA, Reuer J, Kahlmeter G, Foxman B, Marrs CF (2006) The role of horizontal gene transfer in the spread of trimethoprim-sulfamethoxazole resistance among uropathogenic Escherichia coli in Europe and Canada. J Antimicrob Chemother 57:666–672. doi:10.1093/jac/dkl020

    Article  PubMed  CAS  Google Scholar 

  62. Brolund A, Sundqvist M, Kahlmeter G, Grape M (2010) Molecular characterisation of trimethoprim resistance in Escherichia coli and Klebsiella pneumoniae during a two year intervention on trimethoprim use. PLoS One 5:e9233. doi:10.1371/journal.pone.0009233

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Medina AM, Rivera FP, Pons MJ, Riveros M, Gomes C, Bernal M, Meza R, Maves RC, Huicho L, Chea-Woo E, Lanata CF, Gil AI, Ochoa TJ, Ruiz J (2015) Comparative analysis of antimicrobial resistance in enterotoxigenic Escherichia coli isolates from two paediatric cohort studies in lima, Peru. Trans R Soc Trop Med Hyg 109:493–502. doi:10.1093/trstmh/trv054

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Baca AM, Sirawaraporn R, Turley S, Sirawaraporn W, Hol WG (2000) 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. J Mol Biol 302:1193–1212. doi:10.1006/jmbi.2000.4094

    Article  PubMed  CAS  Google Scholar 

  65. Yun M-K, Wu Y, Li Z, Zhao Y, Waddell MB, Ferreira AM, Lee RE, Bashford D, White SW (2012) Catalysis and sulfa drug resistance in dihydropteroate synthase. Science 335:1110–1114. doi:10.1126/science.1214641

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Romano KP, Ali A, Royer WE, Schiffer CA (2010) Drug resistance against HCV NS3/4A inhibitors is defined by the balance of substrate recognition versus inhibitor binding. Proc Natl Acad Sci U S A 107:20986–20991. doi:10.1073/pnas.1006370107

    Article  PubMed  PubMed Central  Google Scholar 

  67. Swedberg G, Castensson S, Skold O (1979) Characterization of mutationally altered dihydropteroate synthase and its ability to form a sulfonamide-containing dihydrofolate analog. J Bacteriol 137:129–136

    PubMed  PubMed Central  CAS  Google Scholar 

  68. Dallas WS, Gowen JE, Ray PH, Cox MJ, Dev IK (1992) Cloning, sequencing, and enhanced expression of the dihydropteroate synthase gene of Escherichia coli MC4100. J Bacteriol 174:5961–5970

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Vedantam G, Nichols BP (1998) Characterization of a mutationally altered dihydropteroate synthase contributing to sulfathiazole resistance in Escherichia coli. Microb Drug Resist 4:91–97

    Article  CAS  PubMed  Google Scholar 

  70. Vedantam G, Guay GG, Austria NE, Doktor SZ, Nichols BP (1998) Characterization of mutations contributing to sulfathiazole resistance in Escherichia coli. Antimicrob Agents Chemother 42:88–93

    PubMed  PubMed Central  CAS  Google Scholar 

  71. Hampele IC, D’Arcy A, Dale GE, Kostrewa D, Nielsen J, Oefner C, Page MG, Schönfeld HJ, Stüber D, Then RL (1997) Structure and function of the dihydropteroate synthase from Staphylococcus aureus. J Mol Biol 268:21–30. doi:10.1006/jmbi.1997.0944

    Article  PubMed  CAS  Google Scholar 

  72. Lopez P, Espinosa M, Greenberg B, Lacks SA (1987) Sulfonamide resistance in Streptococcus pneumoniae: DNA sequence of the gene encoding dihydropteroate synthase and characterization of the enzyme. J Bacteriol 169:4320–4326

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Maskell JP, Sefton AM, Hall LM (1997) Mechanism of sulfonamide resistance in clinical isolates of Streptococcus pneumoniae. Antimicrob Agents Chemother 41:2121–2126

    PubMed  PubMed Central  CAS  Google Scholar 

  74. Padayachee T, Klugman KP (1999) Novel expansions of the gene encoding dihydropteroate synthase in trimethoprim-sulfamethoxazole-resistant Streptococcus pneumoniae. Antimicrob Agents Chemother 43:2225–2230. doi:10.1128/AAC.44.5.1411-1411.2000

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Damrosch D (1946) Chemoprophylaxis and sulfonamide resistant streptococci. JAMA 130:124–128

    Article  CAS  Google Scholar 

  76. Swedberg G, Ringertz S, Sköld O (1998) Sulfonamide resistance in Streptococcus pyogenes is associated with differences in the amino acid sequence of its chromosomal dihydropteroate synthase. Antimicrob Agents Chemother 42:1062–1067

    PubMed  PubMed Central  CAS  Google Scholar 

  77. Sköld O (1976) R-factor-mediated resistance to sulfonamides by a plasmid-borne, drug-resistant dihydropteroate synthase. Antimicrob Agents Chemother 9:49–54. doi:10.1128/AAC.9.1.49

    Article  PubMed  PubMed Central  Google Scholar 

  78. Wise EM, Abou-Donia MM (1975) Sulfonamide resistance mechanism in Escherichia coli: R plasmids can determine sulfonamide-resistant dihydropteroate synthases. Proc Natl Acad Sci U S A 72:2621–2625

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Sundström L, Rådström P, Swedberg G, Sköld O (1988) Site-specific recombination promotes linkage between trimethoprim- and sulfonamide resistance genes. Sequence characterization of dhfrV and sulI and a recombination active locus of Tn21. Mol Gen Genet 213:191–201

    Article  PubMed  Google Scholar 

  80. Radstrom P, Swedberg G (1988) RSF1010 and a conjugative plasmid contain sulII, one of two known genes for plasmid-borne sulfonamide resistance dihydropteroate synthase. Antimicrob Agents Chemother 32:1684–1692. doi:10.1128/AAC.32.11.1684

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Grape M, Sundström L, Kronvall G (2003) Sulphonamide resistance gene sul3 found in Escherichia coli isolates from human sources. J Antimicrob Chemother 52:1022–1024. doi:10.1093/jac/dkg473

    Article  PubMed  CAS  Google Scholar 

  82. Manyahi J, Tellevik MG, Ndugulile F, Moyo SJ, Langeland N, Blomberg B (2016) Molecular characterization of cotrimoxazole resistance genes and their associated integrons in clinical isolates of gram-negative bacteria from Tanzania. Microb Drug Resist 23:37–43. doi:10.1089/mdr.2016.0074

    Article  PubMed  CAS  Google Scholar 

  83. Lever Jr OW, Bell LN, McGuire HM, Ferone R (1985) Monocyclic pteridine analogues. Inhibition of Escherichia coli dihydropteroate synthase by 6-amino-5-nitrosoisocytosines. J Med Chem 28:1870–1874. doi:10.1021/jm00150a019

    Article  PubMed  CAS  Google Scholar 

  84. Lever OW, Bell LN, Hyman C, McGuire HM, Ferone R (1986) Inhibitors of dihydropteroate synthase: substituent effects in the side-chain aromatic ring of 6-[[3-(aryloxy)propyl]amino]-5-nitrosoisocytosines and synthesis and inhibitory potency of bridged 5-nitrosoisocytosine-p-aminobenzoic acid analogs. J Med Chem 29:665–670. doi:10.1021/jm00155a014

    Article  PubMed  CAS  Google Scholar 

  85. Babaoglu K, Qi J, Lee RE, White SW (2004) Crystal structure of 7,8-dihydropteroate synthase from Bacillus anthracis: mechanism and novel inhibitor design. Structure 12:1705–1717. doi:10.1016/j.str.2004.07.011

    Article  PubMed  CAS  Google Scholar 

  86. Hevener KE, Yun MK, Qi J, Kerr ID, Babaoglu K, Hurdle JG, Balakrishna K, White SW, Lee RE (2010) Structural studies of pterin-based inhibitors of dihydropteroate synthase. J Med Chem 53:166–177. doi:10.1021/jm900861d

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Zhao Y, Hammoudeh D, Yun MK, Qi J, White SW, Lee RE (2012) Structure-based design of novel pyrimido[4,5-c]pyridazine derivatives as dihydropteroate synthase inhibitors with increased affinity. ChemMedChem 7:861–870. doi:10.1002/cmdc.201200049

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Zhao Y, Shadrick WR, Wallace MJ, Wu Y, Griffith EC, Qi J, Yun M-K, White SW, Lee RE (2016) Pterin-sulfa conjugates as dihydropteroate synthase inhibitors and antibacterial agents. Bioorg Med Chem Lett 26:3950–3954. doi:10.1016/j.bmcl.2016.07.006

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Qi J, Virga KG, Das S, Zhao Y, Yun MK, White SW, Lee RE (2011) Synthesis of bi-substrate state mimics of dihydropteroate synthase as potential inhibitors and molecular probes. Bioorg Med Chem 19:1298–1305. doi:10.1016/j.bmc.2010.12.003

    Article  PubMed  CAS  Google Scholar 

  90. Raffaello M (1997) Diaminopyrimidines, pharmaceutical compositions containing them and their use as antibacterial. US Patent WO1997020839 A1, 12 June 1997

    Google Scholar 

  91. Schneider P, Hawser S, Islam K (2003) Iclaprim, a novel diaminopyrimidine with potent activity on trimethoprim sensitive and resistant bacteria. Bioorg Med Chem Lett 13:4217–4221. doi:10.1016/j.bmcl.2003.07.023

    Article  PubMed  CAS  Google Scholar 

  92. Kohlhoff SA, Roblin PM, Reznik T, Hawser S, Islam K, Hammerschlag MR (2004) In vitro activity of a novel diaminopyrimidine compound, iclaprim, against Chlamydia trachomatis and C. pneumoniae. Antimicrob Agents Chemother 48:1885–1886. doi:10.1128/AAC.48.5.1885-1886.2004

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Talbot GH, Thye D, Das A, Ge Y (2007) Phase 2 study of ceftaroline versus standard therapy in treatment of complicated skin and skin structure infections. Antimicrob Agents Chemother 51:3612–3616. doi:10.1128/AAC.00590-07

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Sincak CA, Schmidt JM (2009) Iclaprim, a novel diaminopyrimidine for the treatment of resistant gram-positive infections. Ann Pharmacother 43:1107–1114. doi:10.1345/aph.1L167

    Article  PubMed  CAS  Google Scholar 

  95. Sader HS, Fritsche TR, Jones RN (2009) Potency and bactericidal activity of iclaprim against recent clinical gram-positive isolates. Antimicrob Agents Chemother 53:2171–2175. doi:10.1128/AAC.00129-09

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Zhanel G, Karlowsky JA (2009) In vitro activity of iclaprim against respiratory and bacteremic isolates of Streptococcus pneumoniae. Antimicrob Agents Chemother 53:1690–1692. doi:10.1128/AAC.01388-08

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Neuner EA, Ritchie DJ, Micek ST (2009) New antibiotics for healthcare-associated pneumonia. Semin Respir Crit Care Med 30:92–101. doi:10.1055/s-0028-1119813

    Article  PubMed  Google Scholar 

  98. Pelphrey PM, Popov VM, Joska TM, Beierlein JM, Bolstad ESD, Fillingham YA, Wright DL, Anderson AC (2007) Highly efficient ligands for dihydrofolate reductase from Cryptosporidium hominis and Toxoplasma gondii inspired by structural analysis. J Med Chem 50:940–950. doi:10.1021/jm061027h

    Article  PubMed  CAS  Google Scholar 

  99. Popov VM, Chan DCM, Fillingham YA, Atom Yee W, Wright DL, Anderson AC (2006) Analysis of complexes of inhibitors with Cryptosporidium hominis DHFR leads to a new trimethoprim derivative. Bioorg Med Chem Lett 16:4366–4370. doi:10.1016/j.bmcl.2006.05.047

    Article  PubMed  CAS  Google Scholar 

  100. Bolstad DB, Bolstad ESD, Frey KM, Wright DL, Anderson AC (2008) Structure-based approach to the development of potent and selective inhibitors of dihydrofolate reductase from Cryptosporidium. J Med Chem 51(21):6839–6852. doi:10.1021/jm8009124

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Paulsen JL, Liu J, Bolstad DB, Smith AE, Priestley ND, Wright DL, Anderson AC (2009) In vitro biological activity and structural analysis of 2,4-diamino-5-(2′-arylpropargyl)pyrimidine inhibitors of Candida albicans. Bioorg Med Chem 17:4866–4872. doi:10.1016/j.bmc.2009.06.021

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Liu J, Bolstad DB, Smith AE, Priestley ND, Wright DL, Anderson AC (2008) Structure-guided development of efficacious antifungal agents targeting Candida glabrata dihydrofolate reductase. Chem Biol 15:990–996. doi:10.1016/j.chembiol.2008.07.013

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Frey KM, Liu J, Lombardo MN, Bolstad DB, Wright DL, Anderson AC (2009) 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. J Mol Biol 387:1298–1308. doi:10.1016/j.jmb.2009.02.045

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Viswanathan K, Frey KM, Scocchera EW, Martin BD, Swain PW, Alverson JB, Priestley ND, Anderson AC, Wright DL (2012) Toward new therapeutics for skin and soft tissue infections: Propargyl-linked antifolates are potent inhibitors of MRSA and Streptococcus pyogenes. PLoS One 7:e29434. doi:10.1371/journal.pone.0029434

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Keshipeddy S, Reeve SM, Anderson AC, Wright DL (2015) Nonracemic antifolates stereoselectively recruit alternate cofactors and overcome resistance in S. aureus. J Am Chem Soc 137:8983–8990. doi:10.1021/jacs.5b01442

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Scocchera E, Reeve SM, Keshipeddy S, Lombardo MN, Hajian B, Sochia AE, Alverson JB, Priestley ND, Anderson AC, Wright DL (2016) Charged nonclassical antifolates with activity against gram-positive and gram-negative pathogens. ACS Med Chem Lett 7:692–696. doi:10.1021/acsmedchemlett.6b00120

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Reeve SM, Scocchera E, Ferreira JJ, G-Dayanandan N, Keshipeddy S, Wright DL, Anderson AC (2016) Charged propargyl-linked antifolates reveal mechanisms of antifolate resistance and inhibit trimethoprim-resistant MRSA strains possessing clinically relevant mutations. J Med Chem 59:6493–6500. doi:10.1021/acs.jmedchem.6b00688

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Reeve SM, Scocchera EW, G-Dayanadan N, Keshipeddy S, Krucinska J, Hajian B, Ferreira J, Nailor M, Aeschlimann J, Wright DL, Anderson AC (2016) MRSA isolates from United States hospitals carry dfrG and dfrK resistance genes and succumb to propargyl-linked antifolates. Cell Chem Biol 23:1458–1467. doi:10.1016/j.chembiol.2016.11.007

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. School of Pharmacy, University of Connecticut, Storrs, CT, 06269, USA

    Eric Scocchera & Dennis L. Wright

Authors
  1. Eric Scocchera
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dennis L. Wright
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dennis L. Wright .

Editor information

Editors and Affiliations

  1. Department of Chemistry & Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA

    Jed F. Fisher

  2. Department of Chemistry & Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA

    Shahriar Mobashery

  3. Department of Chemistry & Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA

    Marvin J. Miller

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG, part of Springer Nature

About this chapter

Cite this chapter

Scocchera, E., Wright, D.L. (2017). The Antifolates. In: Fisher, J., Mobashery, S., Miller, M. (eds) Antibacterials. Topics in Medicinal Chemistry, vol 26. Springer, Cham. https://doi.org/10.1007/7355_2017_16

Download citation

Publish with us

Policies and ethics

Search

Navigation