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




Names (3+)






Enzyme inhibition
Receptor interactions
Non-specific (i.e pH)
Modes of Action (MOA)



Chemical
Brand/Trade
Generic
Sites of Action


Chemtherapeutic
Pharmacodynamic
Miscellaneous
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)



Acquired




G(-) LPS
Lack target or transport
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-; SulphaAntimetabolites




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 cefBroad Spectrum; Bacteriocidal
MOA




Binds to transpeptidases
No cross linking of NAM-NAM
Prevents resealing
Weak  osmotic lysis
Cephalosporin Family

1st



2nd



Cefaclor
Cefoxitin
3rd



Cefalixin
Cephadroxil
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



Example



Inhibit PGC subunit release
from carrier
Inhibits teichoic acid
synthesis
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


Prevents replication


Cycloserine
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




Elongation





mRNA
30S
50S
P site
A site
Translocation
Peptide bond formation
Termination
Protein Synthesis Inhibition
50S Inhibition
Chloramphenicol




CHPC
BS
Synthetic
MOA



Results


Attaches to 50S ribosome
Interferes with peptide bonds
Inhibits protein synthesis
Side Effects


Aplastic anemia
Can inhibit mitochondrial
protein synthesis
Macrolides



-mycin (usually)
Actinomyces source
Examples





MOA




50S reversible binding
Inhibits elongation
Blocks translocation
Result


Erythromycin
Azithromycin
Clarithromycin
Dithromycin
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



Examples



A: nonpeptide
B: cyclic peptides
A: Dalfopristin
B: Quinupristin
MOA

Group A



Group B


Distort ribosomes
Prevent tRNA binding
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






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


Streptomycin
Gentamicin
Neomycin
Amikacin
Tobramycin
Inhibit protein synthesis by interfering with
translation
Side Effects

Toxicity

CN 8

Kidney
Tetracyclines



-cycline
Streptomyces source
BS



Examples








Bind to 30S subunit reversibly
Block tRNA attachment at A site
Inhibit codon-anticodon interaction
Result


Tetracycline
Doxycycline (semi-synthetic)
Oxytetracycline
Tigecycline
Minocycline
MOA


GN, GP
Rickettsial organisms
Inhibit protein synthesis
Side effects


Affect bone development
Stain teeth in children
Tetracycline MOA
Tetracycline Resistance
Oxazolidinones

New AB


Example




Prevents 30S-50S
assembly
Interferes with mRNA
Disrupts initiation
Results


Linezolid
MOA


-zolid
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





Examples


Naldixic acid
MOA


1st
2nd
3rd
4th
Block A subunit of DNA
gyrase
Results


Bactericidal
GN
Fluroquinolones



-floxacin
Second generation quinolone
Examples



MOA






Bind to DNA gyrase
Bind to Tropoisomerase IV
Result: Blocks DNA


Levofloxacin
Norfloxacin
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


MOA


Rifampicin
Binds to RNA
polymerase
Results

Prevents transcription
Plasma Membrane Disruption
Polypeptides

Example


MOA





Polymixins
 Polymixin B
 Polymixin E (colistin)
Detergents
Replace Mg++ and Ca++
Damage phospholipids
Binds to Lipid A
Results


Alter PM
Cell contents leak out
Antibiotic MOA Summary
Antifungals
Polyenes

MOA




Examples



Inactivatate sterols
Changes membrane
permeability
Leakage of interacellular
components
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




Examples


ssDNA or ssRNA
binds as complementary
strand to mRNA
Blocks translation
Fomivirsen
Use

CMV
Questions?