《药理学》课程PPT教学课件（Antimicrobial Drugs）43b Sulfonamides and other Synthetic Antimicrobial Drugs

FOLATEANTAGONISTS

FOLATE ANTAGONISTS

SyntheticAntimicrobial DrugsSulfonamides Trimethoprim （TMP)

Synthetic Antimicrobial Drugs • Sulfonamides • Trimethoprim ( TMP )

OVERVIEWFolic acid functions as a coenzyme in thetransfer of one-carbonunits required forthesynthesis of thymidine, purines, and some aminoacids and consists of three components: a pteridinemoiety,PABA, and glutamateCOOH-CH2-CH2B---NH-CHH21NE-COOHNOHPteridinePABAGlutamate

I OVERVIEW Folic acid functions as a coenzyme in the transfer of one-carbon units required for the synthesis of thymidine, purines, and some amino acids and consists of three components: a pteridine moiety, PABA, and glutamate

Susceptible bacteria are those that need PABAbecause they are incapable of utilizing folic aciddirectly.Human cells utilize exogenous folic acidexclusively.ThelackofPABAdonotaffectthem

Susceptible bacteria are those that need PABA because they are incapable of utilizing folic acid directly. Human cells utilize exogenous folic acid exclusively. The lack of PABA do not affect them

SulfonamidesThe classification of sulfonamides· Drugs used in general infections:SIZ-SulfisoxazoleSD-SulfadiazineSMZ-Sulfamethoxazole.Drugs used in enteric infections:SASP- Salazosulfapyridine· Drugs used in local infections:SA-Sulfacetamide SodiumSML- SulfamylonSD-Ag-Sulfadiazine Silver

Sulfonamides The classification of sulfonamides • Drugs used in general infections: - Sulfisoxazole SIZ - Sulfadiazine SD - Sulfamethoxazole SMZ • Drugs used in enteric infections: - Salazosulfapyridine SASP • Drugs used in local infections: - Sulfacetamide Sodium SA - Sulfamylon SML - Sulfadiazine Silver SD-Ag

ChemistryThe sulfonamides are derived fromsulfanilamideThe sulfonamidestructureissimilartoPABAPABA is P-aminobenzoic acid forthe synthesis of folicacidinbacteria.The amino group(-NH2) of sulfanilamide nucleus mustbe free.SO,NHCOOHNH2NH2Sulfanilamidep-Aminobenzoicacid(PABA)

Chemistry • The sulfonamides are derived from sulfanilamide • The sulfonamide structure is similar to PABA, PABA is P-aminobenzoic acid for the synthesis of folic acid in bacteria. • The amino group(-NH2) of sulfanilamide nucleus must be free. SO2NH2 COOH NH2 NH2 Sulfanilamide p-Aminobenzoic acid(PABA)

Mechanism of actionCOOH1CH2CH2-NH-CHH,NNH2—一SO2NH21COOHOHNPABAPteridineGlulamateSulfonamidescaninhibitdihydropteroatesynthetasebycompetingwithPABAThebacterial DNAsynthesisisdecreasedThe growth of the bacteria can be inhibited

Mechanism of action • Sulfonamides can inhibit dihydropteroate synthetase by competing with PABA . • The bacterial DNA synthesis is decreased. The growth of the bacteria can be inhibited. NH2 SO2 NH2

Action of SulfonamidesPABApteridineglutamateDihydrofolic acidSulfonamidesSynthetaseFolateDihydrofolic acidreductaseTetrahydrofol ateSynthesis ofThymidylate, etc

Action of Sulfonamides PABA (—) Sulfonamides Folate Tetrahydrofol ate Synthesis of Thymidylate, etc. . Dihydrofolic acid synthetase Dihydrofolic acid reduc tase pteridine glutamate

Spectrum of activity. Gram-positive cocci:-Staphylococcus-Streptococcus-PneumococcusGram-negativeBacteria:-Gonococcus-Meningococcus-Y.Pestis-Hemophilus influenzae-Proteus-Escherichia coli-Shigella-K.Pneumobacillus-Pseudomonas:Other susceptible organisms:-Chlamydia-Nocardia-Plasmodium

Spectrum of activity • Gram-positive cocci: - Staphylococcus - Streptococcus - Pneumococcus • Gram-negative Bacteria: - Gonococcus - Meningococcus - Hemophilus influenzae - Y. Pestis - Escherichia coli - Proteus - Shigella - K. Pneumobacillus - Pseudomonas • Other susceptible organisms: - Chlamydia - Nocardia - Plasmodium

Mechanism of resistanceLowered affinity of dihydropteroatesynthase to sulfonamides;Decreased bacterial permeability or activeefflux of sulfonamides;An alterative metabolicpathwayforSynthesis of an essential metabolite or over-production ofPABA.CROSS-RESISTANCE

Mechanism of resistance Lowered affinity of dihydropteroate synthase to sulfonamides; Decreased bacterial permeability or active efflux of sulfonamides; An alterative metabolic pathway for synthesis of an essential metabolite or over￾production of PABA. CROSS-RESISTANCE