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  3 rd 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 1 st 2 nd 3 rd 4 th Cepha- or cef- Broad Spectrum; Bacteriocidal MOA Binds to transpeptidases No cross linking of NAM-NAM Prevents resealing Weak  osmotic lysis

Cephalosporin Family 1 st Cefalixin Cephadroxil 2 nd Cefaclor Cefoxitin 3 rd Cefdinir Deftibuten 4 th

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 2 nd 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 1 st 2 nd 3 rd 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?