1887

Chapter 26 : Compounds That Interfere with Tetrahydrofolic Acid Biosynthesis

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Ebook: Choose a downloadable PDF or ePub file. Chapter is a downloadable PDF file. File must be downloaded within 48 hours of purchase

Buy this Chapter
Digital (?) $30.00

Preview this chapter:
Zoom in
Zoomout

Compounds That Interfere with Tetrahydrofolic Acid Biosynthesis, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555817794/9781555812584_Chap26-1.gif /docserver/preview/fulltext/10.1128/9781555817794/9781555812584_Chap26-2.gif

Abstract:

Two groups of compounds, the sulfonamides and the 2,4-diaminopyrimidines, e.g., trimethoprim (TMP), interfere with the biosynthesis of tetrahydrofolic acid (THF). Their chemistry and development are treated separately, but their mechanism of action relies on the inhibition of two different enzymes, dihydropteroate synthetase (DHPS) and dihydrofolate reductase (DHFR), which are active in the bacterial biosynthesis of THF. Sulfonamides derived from p-aminobenzenesulfonamide are commonly referred to as sulfa drugs. Sulfonamides are synthetic antibacterial agents with an illustrious history. Chemically, the clinically useful sulfonamides are derived from paminobenzenesulfonamide. The enzyme DHPS catalyzes the displacement of pyrophosphate from the pteridine substrate. It is well established that the sulfonamides mimic p-aminobenzoic acid (PABA), which is the natural substrate required for the biosynthesis of THF. Since it does not enter bacterial cells, bacteria must synthesize dihydrofolic acid (DHF) and THF intracellularly de novo. This difference in the biochemistry of the bacterial cell and the human cell is the basis of the selective toxicity of the sulfonamides. Huovinen indicated that it may be difficult to separate the influences of the transport-related mechanisms on resistance levels. P. aeruginosa has these types of resistance mechanisms, which explains why the potency of TMP and the sulfonamides against P. aeruginosa is limited, with MICs typically in the resistant range. For certain pathogens, TMP-Sulfamethoxazole (SMX) is considered the agent of choice. These include Moraxella catarrhalis, Haemophilus influenzae causing upper respiratory infections and bronchitis, Y. enterocolitica, Aeromonas spp., Burkholderia cepacia, S. maltophilia, and Nocardia spp.

Citation: Mascaretti O. 2003. Compounds That Interfere with Tetrahydrofolic Acid Biosynthesis, p 319-328. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch26
Highlighted Text: Show | Hide
Loading full text...

Full text loading...

Figures

Image of Figure 26.1
Figure 26.1

General structure of the sulfonamide drugs.

Citation: Mascaretti O. 2003. Compounds That Interfere with Tetrahydrofolic Acid Biosynthesis, p 319-328. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch26
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 26.2
Figure 26.2

Metabolic transformation in vivo of prontosil into p-aminobenzenesulfonamide.

Citation: Mascaretti O. 2003. Compounds That Interfere with Tetrahydrofolic Acid Biosynthesis, p 319-328. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch26
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 26.3
Figure 26.3

Sulfonamides and THF biosynthesis in bacteria.

Citation: Mascaretti O. 2003. Compounds That Interfere with Tetrahydrofolic Acid Biosynthesis, p 319-328. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch26
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 26.4
Figure 26.4

Figure 26.4 Chemical structure of folic acid and reduction to DHF and THF catalyzed by the human DHFR in the presence of NADPH.

Citation: Mascaretti O. 2003. Compounds That Interfere with Tetrahydrofolic Acid Biosynthesis, p 319-328. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch26
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 26.5
Figure 26.5

Chemical structure of TMP.

Citation: Mascaretti O. 2003. Compounds That Interfere with Tetrahydrofolic Acid Biosynthesis, p 319-328. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch26
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 26.6
Figure 26.6

Inhibition of bacterial DHFR by TMP.

Citation: Mascaretti O. 2003. Compounds That Interfere with Tetrahydrofolic Acid Biosynthesis, p 319-328. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch26
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 26.7
Figure 26.7

Scheme showing the importance of the essential THF cofactors in the bacterial synthesis of thymidine, purines, glycine, and methionine and how they affect the DNA, RNA, and protein synthesis.

Citation: Mascaretti O. 2003. Compounds That Interfere with Tetrahydrofolic Acid Biosynthesis, p 319-328. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch26
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 26.8
Figure 26.8

Interconversion of the C-1 units carried by THF.

Citation: Mascaretti O. 2003. Compounds That Interfere with Tetrahydrofolic Acid Biosynthesis, p 319-328. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch26
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 26.9
Figure 26.9

Cycle of reaction in the synthesis of dTMP from dUMP. The reaction for regeneration of THF is blocked by TMP, bringing the cycle to a halt with the folate in the inactive dihydro form.

Citation: Mascaretti O. 2003. Compounds That Interfere with Tetrahydrofolic Acid Biosynthesis, p 319-328. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch26
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 26.10
Figure 26.10

Origins of the atoms in the purine ring.

Citation: Mascaretti O. 2003. Compounds That Interfere with Tetrahydrofolic Acid Biosynthesis, p 319-328. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch26
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 26.11
Figure 26.11

Biosynthesis of glycine in bacteria.

Citation: Mascaretti O. 2003. Compounds That Interfere with Tetrahydrofolic Acid Biosynthesis, p 319-328. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch26
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 26.12
Figure 26.12

Regeneration of methionine from homocysteine by transfer of the methyl group of N 5- methyltetrahydrofolate.

Citation: Mascaretti O. 2003. Compounds That Interfere with Tetrahydrofolic Acid Biosynthesis, p 319-328. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch26
Permissions and Reprints Request Permissions
Download as Powerpoint

References

/content/book/10.1128/9781555817794.chap26
1. Fuller, A. T. 1937. Lancet i:194.
2. Tréfouel, J.,, J. Tréfouel,, F. Nitti,, and D. Bovet. 1935. C. R. Soc. Biol. 120:756.
3. Zinner, S. H.,, and K. H. Mayer,. 2000. Sulphonamides and trimethoprim, p. 394404. In G. L. Mandell,, J. E. Bennett,, and R. Dolin, ed., Principles and Practice of Infectious Diseases, 5th ed. Churchill Livingstone, Inc., Philadelphia, Pa.
4. Kucers, A.,, S. M. Growe,, M. L. Grayson,, and J. F. Hoy. 1997. The Use of Antibiotics, 5th ed., p. 806904. Butterworth- Heinemann, Oxford, United Kingdom.
5. Hampele, I.,, A. D’Arcy,, G. E. Dale,, D. Kostrewa,, J. Nielsen,, C. Oefner,, M. G. P. Page,, H. J. Schönfeld,, D. Stüber,, and R. L. Then. 1997. Structure and function of the dihydropteroate synthase from Staphylococcus aureus. J. Mol. Biol. 268:2130.
6. Hardy, L. W.,, J. S. Finer-Moore,, W. R. Montfort,, M. O. Jones,, D. V. Sant,, and R. M. Stroud. 1987. Atomic structure of thymidilate synthase: target for rational drug design. Science 235:448455.
7. Sköld, O. 2000. Sulfonamide resistance: mechanisms and trends. Drug Resist. Updates 3:178189.
8. Dale, G. E.,, C. Broger,, A. D’Arcy,, P. G. Hartman,, R. Hooyt,, S. Jolidon,, I. Kompis,, A. M. Labhardt,, H. Langen,, H. Locher,, M. G. Page,, D. Stuber,, R. L. Then,, B. Wipf,, and C. Oefner. 1997. A single amino acid substitution in Staphylococcus aureus dihydrofolate reductase determines trimethoprim resistance. J. Mol. Biol. 266:2330.
9. De Groot, R.,, M. Sluijter,, A. D. De Bruyn,, J. Campos,, W. H. F. Goessens,, A. L. Smith,, and P. W. M. Hermans. 1996. Genetic characterization of trimethoprim resistance in Haemophilus influenzae. Antimicrob. Agents Chemother. 40:21312136.
10. Huovinen, P. 1997. Increases in rates of resistance to trimethoprim. Clin. Infect. Dis. 24(Suppl. 1):S63S66.
11. Peter, A. V.,, M. du Plessis,, K. P. Klugman,, and S. G. B. Amyes. 1998. New trimethoprim-resistant dihydrofolate reductase cassette, dfrXV, inserted in a class 1 integron. Antimicrob. Agents Chemother. 42:22212224.
12. Pikis, A.,, J. A. Donkersloot,, W. J. Rodriguez,, and J. M. Keith. 1998. A conservative amino acid mutation in the chromosomeencoded dihydrofolate reductase confers trimethoprim resistance. J. Infect. Dis. 178:700706.
13. Huovinen, P. 2001. Resistance to trimethoprim-sulfamethoxazole. Clin. Infect. Dis. 32:16081614.
14. Huovinen, P.,, L. Sundström,, G. Swedberg,, and O. Sköld. 1995. Trimethoprim and sulfonamide resistance. Antimicrob. Agents Chemother. 39:279289.
15. Köhler, T.,, M. Kok,, M. Michea-Hamzehpour,, P. Plesiat,, N. Gotoh,, T. Nishino,, L. Kocjancic Curty,, and J.-C. Pechere. 1996. Multidrug efflux in intrinsic resistance to trimethoprim and sulfamethoxazole in Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 40:22882290.

Tables

Generic image for table
Table 26.1

Generic and common trade names of sulfonamides, trimethoprim, and trimethoprim-sulfonamide combinations, the preparations available, and manufacturers in the United States

Citation: Mascaretti O. 2003. Compounds That Interfere with Tetrahydrofolic Acid Biosynthesis, p 319-328. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch26

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error