Pathophysiology, drug targets and resistance in viruses, (myco)bacteria & fungi

Question 1

Are targets dictated by pathogens or hosts?

Answer 1

pathogens

Question 2

Advantage to have greater evolutionary distance between humans and pathogens

Answer 2

This would allow for them have more different targets which makes it easier to find specific drugs

Question 3

Disadvantage to have closer evolutionary distance between human and pathogen?

Answer 3

tougher to find specific drugs

Question 4

More essential pathogen targets (bigger genomes) means?

Answer 4

more drugs

Question 5

Resistance mechanisms are dictated by?

Answer 5

pathogen or virus

Question 6

Simple genomes of virus have how many genes?

Answer 6

5-50 genes

Question 7

How do viruses acquire resistance?

Answer 7

through mutations in target genes occurring during lower fidelity gene replication

Question 8

What is a resistant mechanism that bacteria and fungi have that viruses do not have?

Answer 8

Viruses do not have efflux pumps because they do not have a specific location for replication so there is no where for the efflux pump to be

Question 9

Where do viruses replicate?

Answer 9

host cell

Question 10

What does having complex genomes of thousands of genes mean for resistance mechanisms in bacteria and fungi?

Answer 10

lots of potential resistance mechanisms

Question 11

What are three ways bacteria and fungi can acquire resistance through?

Answer 11

1. modification of target genes and control elements and amplification of target genes
2. activation of efflux pumps, lowered uptake, lowered activation of prodrugs
3. activation of antibiotic metabolism/inactivation

Question 12

Where does modification of target genes and control elements and amplification of target genes occur?

Answer 12

1. pathogen chromosome or moveable elements like plasmids

2. Although mutations are genetic, most modified antibiotic-target interactions take place in the proteins these encode

Question 13

What type of control occurs in activation of efflux pumps, lowered uptake, lowered activation of prodrugs?

Answer 13

genetic or non-genetic control

Question 14

What type of control occurs in activation of antibiotic metabolism/inactivation?

Answer 14

genetic or non-genetic control

Question 15

What is an advantage of viral targets?

Answer 15

humans can give selectivity

Question 16

What is a disadvantage of viral targets?

Answer 16

small genomes mean few targets

Question 17

What is true about viruses?

a. are always so small they can be seen with light microscope
b. are always obligate parasites of bacteria, archaea, or eukaryotes
c. never have genomes that code for enzymes important in their replication
d. all of the above are true
e. none of the above are true

Answer 17

b. are always obligate parasites of bacteria, archaea, or eukaryotes

Question 18

What are two ways we treat viruses without antivirals?

Answer 18

1. supportive therapy

2. vaccination

Question 19

What is supportive therapy?

Answer 19

rest, fluids, OTC painkilers

Question 20

When is supportive therapy appropriate?

Answer 20

only for mild, resolvable illness

Question 21

What are 4 disadvantages of vaccinations?

Answer 21

1. doesn’t always work
2. constant mutations in viral genome can lead to different antigens
3. for influenza, means you need a vaccine every year
4. for HIV, no vaccine yet developed and approved

Question 22

How do we treat viruses?

Answer 22

antiviral drugs

Question 23

What are 2 main kinds of antiviral drugs?

Answer 23

1. host directed immune therapies, e.g. interferons used in past for HepC
2. Antiviral drugs

Question 24

What are 3 downsides of antivirals?

Answer 24

1. very few good targets available
2. viruses have massive numbers of noisy replications, mutations in target genes can lead to resistance development
3. targets usually species-specific, no real broad spectrum compounds, need species-level identification for treatment

Question 25

What are 2 advantages of | bacterial targets?

Answer 25

1. can give good selectivity | 2. bigger genomes means more targets

Question 26

What is a disadvantage of bacterial targets?

Answer 26

lots of resistance mechanisms

Question 27

What are 3 unique mycobacteria targets?

Answer 27

1. thick waxy cell wall 2. DNA synthesis 3. ATP synthesis

Question 28

What drugs (4) have thick cell wall mycobacteria target?

Answer 28

1. isoniazid 2. ethambutol 3. ethionamide 4. delamanid

Question 29

What drug has DNA synthesis mycobacteria target?

Answer 29

para amino salicylate

Question 30

What drug has ATP synthase mycobacteria target?

Answer 30

bedaquiline

Question 31

What are 3 shared mycobacterial targets?

Answer 31

1. peptidoglycan-difficult so broadly B lactam resistant 2. DNA dependent RNA polymerase 3. protein synthesis (ribosome)

Question 32

What drug has peptidoglycan mycobacterial target?

Answer 32

meropenem

Question 33

What drug has DNA dependent RNA polymerase mycobacterial target?

Answer 33

rifampin and other rifamycins

Question 34

What 5 drugs have protein synthesis mycobacterial targets?

Answer 34

1. fluroquinolones 2. aminoglycosides 3. capreomycin 4. linezolid 5. macrolides

Question 35

What are 2 types of mycobacteria?

Answer 35

1. TB | 2. environmental non-tuberculous mycobacteria (NTMs)

Question 36

What is am exclusively pathogenic mycobacterai that can infect any human, and has no need for host susceptibility?

Answer 36

TB

Question 37

What are drug targets for TB? (7)

Answer 37

1. thick waxy cell wall 2. DNA synthesis 3. ATP synthase 4. peptidoglycan 5. DNA dependent RNA polymerase 6. protein synthesis, ribosome 7. unknown

Question 38

Drugs that target thick waxy cell wall in TB? 5

Answer 38

isoniazid, ethambutol, ethionamide, | delamanid/pretomani

Question 39

Drugs that target DNA synthesis in TB? 1

Answer 39

para amino salicylate

Question 40

Drugs that target ATP synthase in TB? 1

Answer 40

bedaquiline

Question 41

Drugs that target peptidoglycan in TB? 1

Answer 41

meropenem

Question 42

Drugs that target DNA dependent RNA polymerase in TB? 1

Answer 42

rifampin, other rifamycins

Question 43

Drugs that target protein synthesis, ribosome in TB? 4

Answer 43

fluoroquinolones, aminoglycosides, | capreomycin, linezolid

Question 44

Drugs that have unknown targets in TB? 2

Answer 44

pyrazinamide, clofazimine

Question 45

In drug resistant TB which two big drugs do you lose?

Answer 45

isoniazid and rifampin

Question 46

Downside of drug resistant TB

Answer 46

Becomes increasingly difficult to develop an effective non-toxic regimen

Question 47

Environmental non-tuberculous mycobacteria

Answer 47

NTM

Question 48

NTM mainly infects (5)

Answer 48

susceptible patients, CF, COPD, Bronchiectasis, AIDS (rare now)

Question 49

What is the duration of NTM treatment?

Answer 49

long, can be years or incurable

Question 50

What drug is resistant of M. abscessus that makes this very difficult to treat

Answer 50

rifampin

Question 51

Disadvantages of fungal targets? (3)

Answer 51

1. difficult to get selectivity 2. similarity mean few unique targets 3. Resistance mechanisms to most agents known

Question 52

Advantage of fungal targets?

Answer 52

Mostly pathogens of immuno-compromized

Question 53

Fungal drug targets? (3)

Answer 53

1. unique outer cell wall 2. unique sterols in plasma membranes 3. DNA synthesis

Question 54

Drugs that target unique outer cell wall in fungus infections? 1

Answer 54

echinocandins

Question 55

Drugs that target unique sterols in plasma membranes in fungal infections? 2

Answer 55

polyenes (target sterol), azoles | target unique synthetic enzyme

Question 56

Drugs that target DNA synthesis in fungal infections? 1

Answer 56

5 fluorocytosine

Question 57

Which type of fungal resistance do most species have?

Answer 57

intrinsic resistance to some or many classes of | drugs

Question 58

Why do many species have intrinsic resistance?

Answer 58

most drugs being natural products, so many | fungi have ‘seen’ them before