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?