Basics and Mechanisms of Action Flashcards
Chemotherapy
Treatment of disease w/ antibiotics or other chemical agents
Antibiotics Characteristics
- Microbial origins (fungi) classically, some synthetic now
- Low molecular weight
- Spectrum of Activity
a. broad: wide variety of unrelated
b. narrow: few related - Mechanism of action
Basis of Selective Toxicity
- Absence of target from host (inhibit bacteria w/o hurting host
- Permeability differences: antibiotics must be effective at concentrations that don’t hurt the host
- Structural differences in target: ex. different ribosomal subunits
Bacteriostatic agents
Reversibly inhibit bacterial growth; resemble metabolite analogs and act as competitive inhibitors
Bactericidal agents
lethal; may/may not cause cell lysis; generally only effective against growing cells
Often irreversible competitive inhibitors
Minimal Inhibitory Concentration (MIC)
lowest concentration of drug that inhibits more than 99% of bacterial population
Minimal Lethal Dose (MLD)
Lowest concentration of drug that kills more than 99.9% of bacterial population
Drug interactions: Indifference
Combined action of drug A and B is not greater than the more effective drug alone, nor is it less effective
Drug interactions: additive
The effects of A and B sum together
Drug interactions: synergism
Effects of A and B are greater than the sum of A and B. Often occurs with 2 bactericidal drugs
Drug interactions: Antagonism
The effects of A and B together are less than the most effective drug. Often occurs when a bactericidal drug is used with a bacteriostatic drug
Intrinsic antibiotic resistance
The target of the antibiotic is missing
Ex. Vancomycin not effective against mycoplasm b/c no peptidoglycan
Acquired antibiotic resistance: Horizontal gene transfer
Antibiotic target is present but the bacteria acquired a mutation by exchanging genetic material via plasmids or transposable elements
Acquired antibiotic resistance: Spontaneous mutation
Mutations arise spontaneously & randomly in absence of selection
3 Antibiotic Mechanisms of Action
- Target essential metabolic pathway
- Target nucleic acid synthesis
a. Transcription
b. DNA replication - Disrupt bacterial membranes
Sulfonamides/Sulfa drugs
-Broad spectrum bacteriostatic
-Inhibit Folic acid biosynthesis (bacteria must produce via tetrahydrofolic acid), but host can acquire (Selective toxicity)
-Inhibit dihydropteroate synthase
-Structural analog of PABA
Often used w/ trimethoprim that inhibits dihydrofolate reductase (analog of DHFA)
Sulfa drugs w/ Trimethoprim
- Synergism
- Sulfas only block new THFA but old stores can be utilized by bacteria
- Trimethoprim blocks usage of preexisting DHAF
- Together these drugs block both branches
p-aminosalicylic Acid (PAS)
- MOA similar to sulfonamides
- Effective against mycobacterium tuberculosis (sulfas are NOT)
Rifampin ad Rifabutin
- Affecting nucleic acid synth: Inhibition of Transcriptional Initiation
- Bactericidal
- Narrow spectrum: gram positive, Neisseria, mycobacteria
- MOA: binds beta subunit of RNA polymerase, inhibits transcription initiation, but not transcription in progress
- Selective toxicity: Host RNA polymerase not sensitive, mito impermeable
Quinolones
- Affecting nucleic acid synth: Inhibition of DNA replication
- Bactericidal
- Nalidixic acid: narrow for G- UTI
- Ciprofloxacin: broad spectrum against pseudomonas
- MOA: Inhibits DNA gyrase
- Selective toxicity: Humans have no DNA gyrase or topoisiomerase IV
- Resistance: decreased uptake, target mutation
Metronidazole
- Affecting nucleic acid synth: damage DNA structure
- Bactericidal
- MOA: disrupts DNA structure, inhibits DNA replication, DNA breaks and mutations
- Selective toxicity: given as prodrug, and only bacteria have the enzyme to convert to active form
- Uses: narrow spectrum against anaerobic H. pylori giardia lamblia
- Resistance: mutations to oxidoreductases that affect conversion of pro-drug
Polymixins
- Affecting cell membranes
- bactericidal narrow spectrum for pseudomonas
- MOA: hydrophobic tail inserts into cell membrane and hydrophilic head binds polar phosphatidylethanolamine (PE) and lipopolysaccharide (LPS) and disrupts cytoplasmic membrane
- Selective toxicity: host cells have no PE or LPS
- Resistance: G- have lipid A in LPS that makes outer membrane impermeable