Module 3: Therapeutic application of selective toxicity Flashcards
What are the features of the pathogen-host-drug relationship?
- pathogen invades host or host fights pathogen through defence mechanism (Passive Defence, Innate & Adaptive Immunity)
- pathogen forms resistance against drug OR drug selectively targets pathogen
- drug treatment initiated OR drug affects host through PK/PD factors, selective toxicity and alterations in non-pathogenic flora
What are the potential targets for selective antibacterial activity?
- Distinct Cell Wall Structure
- Folate synthesis: distrupt bacterial folate production & inhibit essential components for DNA & RNA synthesis
- Bacterial DNA Replication: drug can inhibit and prevent bacteria from multiplying
- Bacterial Protein Synthesis: 70s ribosome - 30s and 50s subunits
Describe the PD/PK properties of antibacterial drugs
1. Concentration- & Time-dependent effects
2. Bactericidal OR Bacteriostatic
* Kill or Inhibit growth
3. Spectrum of Activity
* influence choice, and dosing schedule of drug
Describe the Narrow & Broad Spectrum of Activity
Narrow Spectrum
* specific drugs targeting gram + or -
* useful when drug agent is known
Broad Spectrum
* targets both gram + & -
* useful when drug target in unknown
Describe the different mechanisms of development of bacterial antimicrobial resistance
Innate Resistance of Bacteria
* Protective mechanism for survival
* Bacteria naturally possess features that hinder drug effectiveness = cell wall, porins, metabolic enzymes, efflux transporters
Acquired Resistance by Bacteria
* Transfer of resistance genes
* Vertical transfer: Resistance genes passed down from parent to offspring
* **Horizontal transfer:** Resistance genes **shared** directly between bacteria through plasmids or conjugation
What factors promote resistance of bacterial antibiotics?
- Incorrect antibiotic use: promotes survival of resistance bacteria
- Antibiotics in the environment: creates selection pressure
- Impact on normal microbiota: Antibiotics disrupt natural gut bacteria = allows resistance pathogens to thrive
What is the mechanism that changes the innate protective mechanisms?
- Point mutations = reduce uptake (gram -ve bacteria)
- Increased production of enzyme that inactivates drug (β-lactamases)
- Reduces affinity for target
- Produces enzymes that increase efflux of drug (p-glycoprotein)
What causes bacterial antimicrobial resistance?
- Overprescribing & incorrect prescription
- Not finishing the full treatment course
- Lack of hygiene and poor sanitation
- Overuse in livestock and fish farming
- Lack of new antibiotics being developed
Identify targets for antiviral therapy in the virus life cycle & possible therapies for each.
Attachment & Entry
* Fusion Inhibitors
* Ion Channel Blockers
Viral Replication
* Polymerase Inhibitors
Assembly & Packaging
* Protease Inhibitors
Release
* Neuraminidase Inhibitors
What is Cytotoxic Chemotherapy?
Non-specific inhibition of DNA replication or Mitosis
Distinguish different mechanisms of cytotoxic cancer chemotherapy
DNA damage
* Alkylating agents
* Intercalating agents
Cell Cycle Disruption
* Topoisomerase inhibitors: interfere with enzymes that unwind DNA for replication
* DNA Synthesis inhibitors: block enzymes involved in DNA synthesis
* Mitosis Inhbitors: prevent cell division by targeting microtubules
What is the mechanism of action of Alkylating agents?
- directly damage DNA
- impact all cell cycle phases
- crosslink DNA strands by guanine alkylation
- prevent replication and transcription
What is the mechanism of action of Intercalating agents?
- anti-tumour antibiotics derived from bacteria
- insert between DNA base pairs = strand breaks = inhibits replication
Antibiotics:
* Anthracyclines (doxorubicin, daunorubicin) = all phases
* Bleomycin = G2 phase
What is the mechanism of action of Topoisomerase inhibitors?
- seperate DNA strands in S phase = leads to strand break
Topoisomerase I inhibitor (Irinotecan)
* makes single strand cuts
* Greater efficacy and lower toxicity than natural alkaloid camptothecin
Topoisomerase II inhibitor (Etoposide)
* makes double stranded cuts
What is the mechanism of action of DNA synthesis inhibitors?
- Inhibits enzymes in DNA synthesis pathway = prevents cell division
- Active during S phase - chromosome copying
Drugs
* Methotrexate: folic acid analogue = inhibits dihydrofolate reductase
What is the mechanism of action of Mitotic inhibitors?
- disrupts microtubule assembly = prevents M phase
Drug
* Paclitaxel: stabalise tubulin polymer & prevent disassembly == arrests cells in M phase == cell death
What is the side effects of each of the cytotoxic cancer drugs?
Alkylating agents
* Increased risk of leukemia, pulmonary fibrosis, renal toxicity.
Intercalating agents
* Dose-limiting myelosuppression, cardiotoxicity (heart damage).
Bleomycin
* Skin pigmentation, pulmonary fibrosis.
Topoisomerase inhibitors
* Diarrhea, secondary leukemia.
DNA synthesis inhibitors
* Gastrointestinal and oral ulcers, renal and liver toxicity.
Mitosis inhibitors
* Neurotoxicity, neuropathy (nerve damage).
Describe the mechanism of action of sulfonamides
- Targets Dihydropteroate synthetase
- Sulfonamides = blocks production of folic acid that is essential for bacterial growth
- Sulfonamides compete with PABA for binding to dihydropteroate synthetase
- sulfonamide binding prevents PABA == hinders folic acid production
- insufficient folic acid = bacteria cannot replicate DNA = die
Human get folic acid from diet and dont rely on same pathway as bacteria
Describe the mechanism of action of β-lactam antibacterial drugs
- mimics the D-Ala-D-Ala end of peptidoglycan
- β-lactam binds to active site of PBP due to structural similarity to D-Ala-D-Ala
- Covalent bonds form between drug & serine residue in PBP == irreversibly inhibiting enzyme
- cell wall weakens = cell death DUE TO lack of transpeptidase = bacteria cant cross-link peptidoglycan strands
Peptidoglycan = essential component of bacterial cell wall
* made of altering sugars (NAM & NAG) w/ attached pentapeptide chains
* D-Ala-D-Ala = terminal end of pentapeptide chain
Transpeptidase (PBP) = enzyme that cross-links peptidoglycan trands using D-Ala-D-Ala as substrate
Describe the mechanism of action of protein synthesis inhibitors
Bacterial Ribosomes = 70S structures = 30S and 50S subunits
Drug targets of 30S subunit
Tetracyclines
* competitive inhibition of tRNA binding
* halts protein synthesis
* bacteriostatic
Aminoglycosides
* Causes error by inserting incorrect amino acids
* bactericidal
Drug targets of 50S subunit
Macrolides
* Block peptide transferase
* prevents protein chain elongation (translocation)
* bacteriostatic/cidal
Chloramphenicol
* inhibits peptide bond formation
* bactericidal
* crosses BBB
What is the mechanism of action of Amantadine used for Influenza?
- Ion channel blockers
- M2 ion channel = important for acidification & dissociation
of virus once inside the cells
What is the mechanism of action of Zanamivir used for Influenza?
- Neuraminidase inhibitors
- Neuraminidase = importance for cleaving (HA/ sialic acid bond) from glycoproteins during shedding phase
What is the vaccination primary approach for Influenza?
- target the Hemagglutinin of range of seasonally circulating viruses
What is the mechanism of action of drugs used for Herpes?
Viral DNA polymerase inhibitor
* target viral genomic replication in host cell
* nucleoside analogue = competitive inhibition = prevents virus’s ability to replicate DNA
* prodrug = activation by viral thymidine kinase
Acyclovir = Viral DNA polymerase inhibitor
* Guanine analogue
* prodrug = converted by viral thymidine kinase TO monophosphate TO host cell conversion TO triphosphate
* Triphospho-acyclovir = competes with native substrate for HSV specified DNA polymerase
* missing 3’-OH = prevents further viral DNA synthesis
