Antimicrobial Agents Mohammad Reza Fazeli, PharmD, PhD Professor of Microbiology Department of Drug...
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Antimicrobial AgentsMohammad Reza Fazeli, PharmD, PhDProfessor of MicrobiologyDepartment of Drug and Food ControlFaculty of PharmacyTehran University of Medical Sciences
Overview of Antibiotics as Therapeutic AgentsSelective Inhibition/Toxicity Due to the differences in structure and metabolic pathwaysHarm microorganisms, not the hostFour major sites:Cell wallRibosomesDNACell membrane
Spectrum of ActivityBroad Spectrum Antibiotics:Effective against many types Example: Tetracycline
Narrow Spectrum Antibiotics:Effective against very few types Example: Penicillin
Bactericidal v. BacteriostaticBactericidal:
Used when the host defense mechanisms are impaired
Used when the host defense mechanisms are intact
MECHANISMS OF ACTION OF MAJOR GROUPS OF ANTIBIOTICS
STRUCTURE OF -LACTAM ANTIBIOTICS
Penicillin HomeLooks like a house with a new room added to the sideThink of the R-group as of an antennaChanging antennae and or finishing the basement will create better homes (penicillins)
[Penicillin] Home Improvement Project Adding a new antenna creates broad spectrum penicillins Example: Ampicillin
Adding additional antennae and finishing the basement creates cephalosporinsExample: 1st, 2nd, 3rd, & 4th generation cephalosporins
SPECTRUM OF ACTIVITY OF CEPHALOSPORINS
MECHANISM OF ACTION OF -LACTAM ANTIBIOTICS
-Lactam antibiotics inhibit the formation of peptidoglycan cross-links in the bacterial cell wall, but have no direct effect on cell wall degradation
The -lactam moiety of penicillin binds to the enzyme (transpeptidase) that links the peptidoglycan molecules in bacteria. The enzymes that hydrolyze the peptidoglycan cross-links continue to function, which weakens the cell wall of the bacterium
Bacteria constantly remodel their peptidoglycan cell walls, simultaneously building and breaking down portions of the cell wall as they grow and divide
Gram-positive bacteria are called protoplasts when they lose their cell walls. Gram-negative bacteria do not lose their cell walls completely and are called spheroplasts after treatment with penicillin
-lactam antibiotics are ineffective against protoplasts and spheroplasts:
MECHANISMS OF ACTION OF ANTIRIBOSOMAL ANTIBIOTICS
Inhibition of Protein SynthesisAnti-ribosomal antibiotics impair ribosomes by binding to either 50S or 30S ribosomal subunits Ribosomes are essential for translation of mRNA into proteinsNo translation No protein synthesisNo protein synthesis No growth
MECHANISM OF ACTION OF SULFONAMIDES AND TRIMETHOPRIM
Folic acid (also known as folate , vitamin M, vitamin B9, vitamin Bc or folacin are forms of the water-soluble vitamin B9.
Folic acid is itself not biologically active, but its biological importance is due to tetrahydrofolate and other derivatives after its conversion to dihydrofolic acid in the liver.
Vitamin B9 (folic acid and folate) is essential for numerous body functions. The human body needs folate to synthesize DNA, repair DNA, and methylate DNA as well as to act as a cofactor in certain biological reactions. It is especially important in aiding rapid cell division and growth, such as in infancy and pregnancy. Children and adults both require folic acid to produce healthy red blood cells and prevent anemia.
Mechanisms of Resistance
Genetic MechanismsChromosome-mediatedDue to spontaneous mutation: in the target molecule in the drug uptake systemPlasmid-mediatedCommon in Gram-negative rodsTransferred via conjugationMultidrug resistanceTransposon-mediated
Non-Genetic MechanismInaccessibility to drugs (e.g., abscess, TB lesion)
Stationary phase (insusceptible to inhibitors of cell wall synthesis)
Protoplasts and spheroplasts (insusceptible to inhibitors of cell wall synthesis)
The End Result of Genetically Conferred Resistance
Production of drug-inactivating enzymes
Modification of target structures
Alteration of membrane permeability
Resistance to Beta-LactamsGram +
Alteration of the transpeptidase enzyme
Alteration of porins
How can we test for susceptibility/resistance?
Antibiotic Susceptibility TestingDilution Method
Disc Diffusion Method
Dilution MethodPrepare two fold [antibiotic] dilutions Add 1/2 a million bacterial cells per tube Incubate overnight Check for turbidityEstablish the MIC: The lowest concentration of the drug that prevented the bacterial growth (no turbidity)
Disc Diffusion MethodSeed agar plates with bacteria in questionPlace antibiotic-discs over the seeded plateIncubate overnight Measure the inhibition zonesRelate the results to the zones given in the interpretive chartThere is an inverse relationship between the MICs and zone diameters
Therapeutic Index =Max. Safely Achievable Level MIC