chemotherapeutic agents antimicrobials and antibiotics
TRANSCRIPT
Chemotherapeutic Agents
Antimicrobials and Antibiotics
Normal Microbiota
Body Cavities Closed = free of microbes Open = normal flora
Regions Skin Mouth (teeth/gums) GI Genitourinary
Upper = sterile Perineum
Bacterial Groups
Microbial Pathogenicity Cause of disease Means
Invasiveness Toxigenesis
Stages Colonization Adherence
Nonspecific (dock) Specific (anchor)
Invasion Enzymes
Spread Digest
Toxins
Definitions
Chemotherapy Antimicrobials Antibiotics Synthetic Drugs Selective Toxicity
Paul Ehrlich
Antibiotic Development
AB Natural Source
Fungal molds Bacteria
Bacillus Actinomycetes
Chemotherapeutic Chemical
Semi-synthetic Hybrid
Drug Basics Classification
Chemtherapeutic Pharmacodynamic Miscellaneous
Names (3+) Chemical Brand/Trade Generic
Sites of Action Enzyme inhibition Receptor interactions Non-specific (i.e pH)
Modes of Action (MOA) Pharmakokinetics Stimulate/Depress/Kill
Effects Theruapeutic Adverse
Antimicrobial Characteristics Toxicity MOA Spectrum
BS (both GP and GN) NS (GP or GN) Limited spectrum
Target Tissue Adverse Effects Resistance Route of Administration
Mechanism of Action (MOA)
Effectiveness of AB
Route of Administration Uptake Clearance Susceptibility Dosage
Exceed MIC Therapeutic Selective Toxicity
Adverse Drug Reactions (ADR)
AB and Sx
Other Drug Considerations
Availability Stability Cost
MOA
Cell Wall Cell Membrane DNA Protein Synthesis
30S 50S
Metabolites
Antimicrobial Resistance
Natural (Inherent) G(-) LPS Lack target or transport
Acquired Mutation Horizontal transfer
Vertical Horizontal
Transformation Transduction Conjugation
Plasmids
R-Plasmid
AB resistance
“Super Bugs”
Kirby-Bauer Disk Diffusion
MH agar AB disks MIC Table
Zone diameter Classified
Susceptible Intermediate Resistant
Metabolite Inhibition
Sulfa Drugs
Sulfonamides
Sulfa-; Sulpha- Antimetabolites
Structural Analogs Decrease folic acid
Bacteriostatic Side Effects
Allergic KCS
PABA
Competitive Enzyme Inhibition PABA Folic Acid Folic Acid (B vitamin) Synthesis of N bases
TMPS actions as above Trimethoprim inhibits conversion of folic acid to its active form
Antimetabolite Action
TMPS
BS Block pathway of
synthesis for tetrahydrofolic acid No DNA No RNA
Competitive antagonism Sulfa first enzyme Trimethoprim 3rd enzyme Synergistic
Cell Wall Synthesis Inhibitors
Sir Alexander Fleming
Beta-Lactams
Penicillin Family Beta-lactams Penicillium mold source -cillin MOA
Inhibits PGC synthesis Prevents cross-linking by
transpeptidase Mimicks D-alanine at active
enzyme site Bacteriocidal G(+) Adverse Rxn = allergies Penicillin G, Penicillin V, Oxacillin,
Ampicillin, Cloxacillin, Ticarcillin,Nafcillin, Dicloxacillin, Carbenicillin
Inhibition of Cell Wall Synthesis
Prevent cross linking Binds to transpeptidases
Add new monomers Reseal wall
Osmotic Lysis Bacterial Resistance
Penicillinase MRSA VRSA
Beta Lactamases Cephalosporinases
Beta-Lactam Inhibition
Beta-Lactamase Inhibitors
Clavulanic acid Noncompetitive
inhibitor of penicillinase Destroys enzyme
Carbapenems
-penem Imipenem
Beta-lactam BS Cell wall synthesis
Cephalosporins Modified B-lactam ring (6) Modified R groups Sewer fungus source Generations
1st
2nd
3rd
4th Cepha- or cef- Broad Spectrum; Bacteriocidal MOA
Binds to transpeptidases No cross linking of NAM-NAM Prevents resealing Weak osmotic lysis
Cephalosporin Family
1st
Cefalixin Cephadroxil
2nd
Cefaclor Cefoxitin
3rd
Cefdinir Deftibuten
4th
Glycopeptides Examples
Vancomycin Teichoplanin
MOA Bind to cell wall peptides Block cross-linking of
transpeptidases (Alanine-Alanine) Blocks transglycolation
NAM-NAG bond Result
Weak cell wall Osmotic lysis Bacteriocidal GP
VRSA has developed
Polypeptides
Some can inhibit cell wall synthesis Inhibit PGC subunit release
from carrier Inhibits teichoic acid
synthesis Example
Bacitracin NS: GP Topic Use
Skin Ophthalmic
Bacitracin MOA
Bactoprenol assembles new monomers for the cell wall in the PM
Bacitracin binds to Bactoprenol in PM
Blocks dephosphorylation(must loose 2nd Phosphate)
No monomers can inserted into cell wall
Osmotic lysis
Inhibition of AFB
MOA Disrupt cell wall synthesis
Cycloserine Prevents replication
Clofazimine Disrupt Waxy layer
Mycolic acid and Arabinogalactan Examples
Isoniazid Ethambutal
Mycobacterium Multidrug Therapies
TB resistance
Ribosomes
Protein Synthesis Steps Transcription
DNA mRNA RNA polymerase
Translation Initiation
mRNA 30S 50S
Elongation P site A site Translocation Peptide bond formation
Termination
Protein Synthesis Inhibition
50S Inhibition
Chloramphenicol
CHPC BS Synthetic MOA
Attaches to 50S ribosome Interferes with peptide bonds
Results Inhibits protein synthesis
Side Effects Aplastic anemia Can inhibit mitochondrial
protein synthesis
Macrolides -mycin (usually) Actinomyces source Examples
Erythromycin Azithromycin Clarithromycin Dithromycin
MOA 50S reversible binding Inhibits elongation Blocks translocation
Result Inhibit protein synthesis
G(+) and select G(-) [resp]
Erythromycin
Macrolide MOA
Lincosamides
Semisynthetic Actinomyces source Example
Clindamycin Lincomycin
G(+), some anaerobes MOA
Bind to 50S Block elongation Inhibits protein synthesis
Streptogramins Two Groups
A: nonpeptide B: cyclic peptides
Examples A: Dalfopristin B: Quinupristin
MOA Group A
Distort ribosomes Prevent tRNA binding
Group B Block translocation
Results Inhibit protein synthesis Synergistic if both groups used
30S Inhibition
Aminoglycosides -mycin (usually) Streptomyces source NS: G(-) but some have BS Examples
Streptomycin Gentamicin Neomycin Amikacin Tobramycin
MOA Binds to 30S, irreversibly Changes shape of 30S 50S can not bind Interferes with initiation Misreads mRNA codons Wrong AA inserted by tRNA
Results Inhibit protein synthesis by interfering with
translation Side Effects
Toxicity CN 8 Kidney
Tetracyclines -cycline Streptomyces source BS
GN, GP Rickettsial organisms
Examples Tetracycline Doxycycline (semi-synthetic) Oxytetracycline Tigecycline Minocycline
MOA Bind to 30S subunit reversibly Block tRNA attachment at A site Inhibit codon-anticodon interaction
Result Inhibit protein synthesis
Side effects Affect bone development Stain teeth in children
Tetracycline MOA
Tetracycline Resistance
Oxazolidinones New AB
-zolid Example
Linezolid MOA
Prevents 30S-50S assembly
Interferes with mRNA Disrupts initiation
Results Inhibits translation
Use G(+) MRSA / VRSA
Ribosome Inhibition Summary
Bacterial Resistance
Pump out AB (efflux) Methylate Ribosomes
Obscure target Block binding site
Modify AB so it can’t bind to ribosome target
Nucleic Acid Inhibition
Quinolones Generations
1st
2nd
3rd
4th Examples
Naldixic acid MOA
Block A subunit of DNA gyrase
Results Bactericidal GN
Fluroquinolones -floxacin Second generation quinolone Examples
Levofloxacin Norfloxacin
MOA Bind to DNA gyrase Bind to Tropoisomerase IV
Result: Blocks DNA Repair Replication Transcription
Bacteriocidal BS
DNA gyrase
Adverse Effects
Bacterial Resistance
Modify DNA gyrase Bacterial synthesis of
sort DNA segments to trick quinolones
Metronidizole
Activated by bacteria Nicks in DNA to
fragment strand Used in anaerobic
infections Trade Name
Flagyl
Rifampin
Semi-synthetic GN and Mycobacteria Example
Rifampicin
MOA Binds to RNA
polymerase
Results Prevents transcription
Plasma Membrane Disruption
Polypeptides
Example Polymixins
Polymixin B Polymixin E (colistin)
MOA Detergents Replace Mg++ and Ca++ Damage phospholipids Binds to Lipid A
Results Alter PM Cell contents leak out
Antibiotic MOA Summary
Antifungals
Polyenes MOA
Inactivatate sterols Changes membrane
permeability Leakage of interacellular
components Examples
Amphotericin Nystatin
Results Antifungal
-static -cidal Dose dependant
Fungal Cell Walls
Helminths
Protozoa
Pentamide
MOA Binds to prokaryote DNA Inhibits transcription and
translation Antiprotozoal
Examples Pentamide Pentam Pneumopent
Antivirals
Antisense Nucleic Acids
MOA ssDNA or ssRNA binds as complementary
strand to mRNA Blocks translation
Examples Fomivirsen
Use CMV
Questions?