Pathophysiology, drug targets & resistance (Timmins)

Question 1

Resistance mechanisms in Viruses

Answer 1

• Simple genomes (less targets)

- Mutations in target genes

Question 2

Why do Viruses NOT have efflux pumps?

Answer 2

• Efflux pumps require energy

- Viruses do not make ATP

Question 3

Resistance mechanisms in Bacteria & Fungi

Answer 3

• Modification of target genes
• Activation of efflux pumps
• Activation of abx metabolism/inactivation

Question 4

What is a plasmid?

Answer 4

-A moveable piece of chromosome from a pathogen

Question 5

Viral Drug Targets

Answer 5

• Very different from humans (good selectivity)

- Small genomes (very few targets)

Question 6

Why are viruses always obligate parasites?

Answer 6

• They lack key enzymes for essential genes

- These represent as drug targets

Question 7

How can you treat viruses without antivirals?

Answer 7

• Supportive therapy: rest, fluids, OTC pain killers

- Vaccinations

Question 8

How do we treat viruses

Answer 8

• Host directed immune therapies

- Antiviral drugs

Question 9

What are the downsides of antivirals?

Answer 9

• Very few good targets available
• Mutations in target genes can lead to resistance development
• Targets are usually species specific, no “Broad spectrum” antivirals

Question 10

What is a way to decrease drug resistance

Answer 10

• Multidrug therapy

- Hit the virus in multiple spots and they won’t know what to mutate

Question 11

Viral life cycle

Answer 11

• Attaches to host cell
• Gains entry into host cell
• Viral DNA is formed via reverse transcriptase
• Viral DNA integrates with host DNA
• New Viral RNA is ready to go infect new cells

Question 12

Bacterial drug targets

Answer 12

• Very different from humans (good selectivity)
• Bigger genomes (more targets)
• Lost of resistance mechanisms (BAD)

Question 13

Unique mycobacteria targets

Answer 13

• Thick waxy cell wall
• DNA synthesis
• ATP synthase

Question 14

Shared mycobacterial targets

Answer 14

• Peptidoglycan
• DNA dependent RNA polymerase
• Protein Synthesis

Question 15

Drugs that target the thick waxy wall of mycobacteria

Answer 15

• Isoniazid
• Ethambutol
• Ethionamide
• Delamanid

Question 16

Drugs that target DNA synthesis of mycobacteria

Answer 16

-Para amino salicylate

Question 17

Drugs that target ATP synthase of mycobacteria

Answer 17

-Bedauiline

Question 18

Drugs that target peptidoglycan of mycobacteria

Answer 18

-Meropenem

Question 19

Drugs that target DNA dependent RNA polymerase of mycobacteria

Answer 19

-Rifampin

Question 20

Drugs that target Protein synthesis of mycobacteria

Answer 20

• Fluoroquinolones
• Aminoglycosides
• Capreomycin
• Linezolid
• Macrolides

Question 21

Drug resistant TB

Answer 21

• Loose the big two

- No isonlazid or rifampin

Question 22

NTM TB

Answer 22

-Lose several drugs! 
What will still work? 
-Ethambutol
-Bedaquiline
-Rifampmin 
-Aminoglycosides
-Macrolides

Question 23

Mycobacterial resistance good and bad news

Answer 23

• Good news:
  1) No plasmid related resistances
  2) Transmission of resistance is rare
• Bad news:
  1) Lots of intrinsic resistance

Question 24

Fungal Targets

Answer 24

• Very similar to humans (poor selectivity)
• Few unique targets (BAD)
• Lots of resistance (Bad)
• Most pathogens only effect immunocompromised… (good)

Question 25

Fungal Drug Targets

Answer 25

• Echinocandins (outer cell wall)
• Polyenes (Sterols found in fungi)
• Azoles (Sterols found in fungi)
• 5 FU (DNA synthesis)

Question 26

Fungal drug resistance

Answer 26

• Intrinsic resistance
• Mutation in FKS genes (echinocandins)
• cyp51a gene (Azoles)
• Activate 5FC to 5 Fluorouracil (5FC)

Question 27

What we need to do

Answer 27

• Stop using abx in agricultural
• Make vaccines for viruses
• Make knew abx
• Vaccines for fungi too?
• Host directed therapies: enhance our responses to the pathogens