Lecture 22

• antiviral drugs

  acyclovir

  xofluza

  tamiflu
• acyclovir

  inhibits DNA polymerase of herpes viruses
• Influenza

  Tamiflu - blocks neuraminidase

  Xofluza - blocks RNA replicase, inhibiting replication and translation of viral RNA
• anti - HIV drugs

  major goal of antiretroviral therapy (ART) is reducing viral loads

  drugs and targets:

  • Azidothymidine
  • Integrase inhibitors
  • Ritonavir
• Azidothymidine (AZT)

  blocks reverse transcriptase, mistakes AZT for thymidine, stops DNA chain growth
• integrase inhibitors

  blocks integrase, integrates DNA copy into host DNA provirus
• Ritonavir

  blocks protease, processes viral polypeptides into proteins for virion assembly
• PrEP - anti HIV drug

  preexposure prophylaxis

  Descovy, Truvada

  contain compounds that function as analogs (similar to AZT)
• COVID treatment

  Paxlovid

  2 medication that target covid protease
• antiprotozoan drugs

  malaria

  • chloroquine
  • malorone

  Metronidazole (Flagyl)

  • Giardia
  • prodrug
• Malaria

  Chloroquine - blocks heme polymerization

  malorone - blocks electron transport, pyrimidine synthesis
• Metronidazole 


  Giardia (and some Helicobacter)

  prodrug - harmless until activated, enters pathogen, activated leads to nicking of pathogen DNA
• superbugs

  Vancomycin resistant Enterococcus (VRE)

  Methicillin resistant Staphylococcus aureus (MRSA)
• VRE

  vanA gene - encodes enzyme that replaces D-ala with D-lactate
• MRSA

  mecA gene - encodes PBP resistant to penicillin
• mechanisms of drug resistance

  R plasmids can be transferred by transformation and conjugation
• antibiotics don't mutate microbes, but rather create environments that select for antibiotic resistant mutants
• overcoming drug resistance

  dont treat viral infections with antibacterials

  give drug in high concentrations

  give two or more drugs at same time

  • ex: Augmentin = Amoxicillin + Clavulanic acid
• new antibiotics

  most in use today come from a few bacteria and fungi

  need to identify new antibiotic producing microbes
• new targets

  two component signaling? quorum sensing?
• new vaccines

  Cholera, malaria, HIV
• new approaches

  listex

  spray on fruit and vegetables

  phage therapy
• chickenpox

  varicella - zoster virus

  family: Herpesviridae

  inhalation or conjunctiva of eye

  spreads via blood, neuronal

  about 10 days infection of skin leads to vesicular rash
• chickenpox treatment

  largely supportive

  avoid aspirin (linked to reyes syndrome)

  Current drugs approved for therapy include nucleoside analogues that target the viral DNA polymerase and depend on the viral thymidine kinase for their activation.
• chickenpox prevention

  attenuated (live) vaccine
• vaccines - attenuated

  live but avirulent

  inactivate specific genes

  can reproduce, but weakened

  humoral and cell mediated

  drawback: may revert

  ex: chickenpox, MMR, flu
• vaccines - inactivated

  killed

  chemicals or heat

  induce humoral

  drawback: requires booster

  ex: rabies, flu
• herd immunity

  protection of unvaccinated people in a population where most people are vaccinated due to lessened risk of disease transmission
• what percent of population to achieve herd immunity

  depends on pathogen

  highly contagious diseases such as Pertussis and measles requires 80-90%
• shingles (zoster)

  individuals who recover from chickenpox are often resistant to disease

  viral dna can reside in dormant state in nuclei of nerves, sensory neurons (latency)

  immunocompromised state (age, organ transplant, AIDS, stress) can reactivate virus - leading to shingles
• shingles vaccine

  zostavax - live attenuated

  shingrix - viral glycoprotein
• varicella (chickenpox) viruses migrate up sensory nerve

  herpes zoster (shingles) activation of virus in ganglion due to stress
• influenza

  family: Orthomyxoviridae

  negative ssRNA, segmented genome

  must bring in RNA replicase

  converts to positive used as mRNA
• influenza replication cycle

  attachment - hemagglutinin

  entry - endocytosis

  release via budding - neuraminidase
• changes in antigenicity of influenza viruses- minor

  mutations in viral genes in single strain

  basis: viral RNA replicase - error prone

  can cause epidemic - sudden increase in disease
• antigenic shift - major

  different strains (animal and human), infect cell, genomes reassort, new strain, spread to human who have no immunity

  can cause pandemic - increase in disease in large, geographically widespread population

  ex: 1918 spanish flu = 50 mil deaths
• COVID

  family: Coronaviridae

  large family, infecting many animal hosts (7 strains infect humans)

  strain: Sars - cov - 2

  primary spread: respiratory droplets
• covid structure

  enveloped, linear, positive ssRNA

  viral RNA replicase to replicate

  host receptor : ACE2
• covid testing

  RTPCR

  Serology (antibody)

  antigen tests use labeled antibody to detect nucleoprotein (N)
• covid vaccines - moderna and pfizer

  mRNA vaccines

  encoding sars cov 2 spike protein

  encolsed in lipid nanoparticle