Antimicrobial chemotherapy, agents and mechanisms Flashcards
To ensure understanding of the concepts of antimicrobial chemotherapy To revise and extend the classes of antimicrobials their mechanisms of action To describe common laboratory sensitivity testing of antimicrobials To describe the basis of antimicrobial resistance
Antimicrobial agents
Aimed at
Two types
Controlling specific infecting organisms
Broad and narrow spectrum
Broad spectrum G+ and G- useful
Narrow - primarily useful against only certain species of bacteria
Therapeutically useful if target is
Most antibiotics are directed against
Not present in man
Microbe has higher affinity for drug than man
Bacterial cell wall synthesis, protein synthesis, bacterial nucleic acid synthesis
Selective toxicity
Expressed by
Drug is safer with
Highly effective against toxin but limited toxicity to humans
Therapeutic index - ratio of toxic dose to therapeutic dose
Higher index
Clinically useful characteristics
- It should have a wide spectrum of activity with the ability to destroy or inhibit many different species of pathogenic organisms.
- It should be nontoxic to the host and without undesirable side effects.
- It should be nonallergenic to the host.
- It should not eliminate the normal flora of the host.
- It should be able to reach the part of the human body where the infection is occurring.
- It should be inexpensive and easy to produce.
- It should be chemically-stable (have a long shelf-life).
- Microbial resistance is uncommon and unlikely to develop.
Classification of antimicrobials
Classified by
Chemical structure
Target site
Whether they are bactericidal or bacteriostatic
Testing antibiotics
Methods
Result
MIC/MBC
Disc diffusion on agar
Clear zones around antibiotic application indicate sensitivity to antibiotic
Minimal inhibitory concentration
Minimal bactericidal concentration
MIC/MBC in liquid
Main targets for antimicrobials
Cell wall - peptidoglycan Protein synthesis - ribosomes or enzymes Metabolic pathways DNA Membranes Enzymes
Cell wall
Most antimicrobials
Peptidoglycan outlines lipid bilayer
Unique structure
Cross-linked with amino acids to improve strength
Act against cross-linking and affect interactions between NAM and NAG
Main classes of anti peptidoglycan agent are
Beta lactams - penicillins and cephalosporins
Glycopeptides - vancomycin and teicoplanin
Cycloserine - inhibits alanine racemase and D-alanine ligase
Cycloserine used for
Targets
TB treatment - structural analogue of D-alanine
Two enzymes involved in th cytosolic stages of PEPTG synthesis
Beta lactam antibiotics
Structure
Function
Examples
Bactericidal compounds
Beta lactam ring and inhibit normal cell wall formation
Beta lactam ring can have different structures attached
- penicillins, cephalosporins
Inhibit peptidoglycan formation
- vancomycin - effective against gram +ve
- inhibits formation of cross linkages - beta lactam ring binds to penicillin binding protein which usually catalyses formation of cross linking - acts as competitive inhibitor
Penicillin
Structure
Function
Mimics structure of D-ala-D-ala
Inhibits formation of peptidoglycan cross links in the bacterial cell wall
- BINDING of the 4 membered B lactam ring of penicillin to DD-TRANSPEPTIDASE penicillin binding protein
Cross links are not catalysed –> cell death
Vancomycin
Effective against
Binds to
resistance??
Gram positive organisms
D-alanyl D-alanine dipeptide on side chain of newly synthesised peptidoglycan subunits
subunits not incorporated into cell wall
In resistant strains there s a different amino acid at the end of each chain
vancomycin cannot bind and cell lysis doesn’t occur
Protein synthesis
Dna as template
mRNA processed and binds to ribosomes 30s and 50s
tRNA carries amino acids to mRNA
Base pairing occurs and nascent peptide chain grows
Bind to 30s subunit and cause misreading of genetic code
Tetracyclines - inhibit binding of tRNA to mRNA - ribosome complex - amino acids are not transported to form chain
Erythromycin blocks exit of formed chain
Fusidic acid binds to elongation factor
Blocks attachment to chain therefore blocks chain from growing
Erythromycin
Binds to a molecule in 50s subunit blocking exit of nascent polypeptide chain
Fusidic acid - elongation factor G - bacterial protein needed for translocation on bacterial ribosome after peptide bond formation during protein synthesis
Fusidic acid binds EFG preventing protein synthesis