Pathophysiology, drug targets and resistance in viruses, (myco)bacteria & fungi Flashcards
Are targets dictated by pathogens or hosts?
pathogens
Advantage to have greater evolutionary distance between humans and pathogens
This would allow for them have more different targets which makes it easier to find specific drugs
Disadvantage to have closer evolutionary distance between human and pathogen?
tougher to find specific drugs
More essential pathogen targets (bigger genomes) means?
more drugs
Resistance mechanisms are dictated by?
pathogen or virus
Simple genomes of virus have how many genes?
5-50 genes
How do viruses acquire resistance?
through mutations in target genes occurring during lower fidelity gene replication
What is a resistant mechanism that bacteria and fungi have that viruses do not have?
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
Where do viruses replicate?
host cell
What does having complex genomes of thousands of genes mean for resistance mechanisms in bacteria and fungi?
lots of potential resistance mechanisms
What are three ways bacteria and fungi can acquire resistance through?
- modification of target genes and control elements and amplification of target genes
- activation of efflux pumps, lowered uptake, lowered activation of prodrugs
- activation of antibiotic metabolism/inactivation
Where does modification of target genes and control elements and amplification of target genes occur?
- pathogen chromosome or moveable elements like plasmids
2. Although mutations are genetic, most modified antibiotic-target interactions take place in the proteins these encode
What type of control occurs in activation of efflux pumps, lowered uptake, lowered activation of prodrugs?
genetic or non-genetic control
What type of control occurs in activation of antibiotic metabolism/inactivation?
genetic or non-genetic control
What is an advantage of viral targets?
humans can give selectivity
What is a disadvantage of viral targets?
small genomes mean few targets
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
b. are always obligate parasites of bacteria, archaea, or eukaryotes
What are two ways we treat viruses without antivirals?
- supportive therapy
2. vaccination
What is supportive therapy?
rest, fluids, OTC painkilers
When is supportive therapy appropriate?
only for mild, resolvable illness
What are 4 disadvantages of vaccinations?
- doesn’t always work
- constant mutations in viral genome can lead to different antigens
- for influenza, means you need a vaccine every year
- for HIV, no vaccine yet developed and approved
How do we treat viruses?
antiviral drugs
What are 2 main kinds of antiviral drugs?
- host directed immune therapies, e.g. interferons used in past for HepC
- Antiviral drugs
What are 3 downsides of antivirals?
- very few good targets available
- viruses have massive numbers of noisy replications, mutations in target genes can lead to resistance development
- targets usually species-specific, no real broad spectrum compounds, need species-level identification for treatment
What are 2 advantages of
bacterial targets?
- can give good selectivity
2. bigger genomes means more targets
What is a disadvantage of bacterial targets?
lots of resistance mechanisms
What are 3 unique mycobacteria targets?
- thick waxy cell wall
- DNA synthesis
- ATP synthesis
What drugs (4) have thick cell wall mycobacteria target?
- isoniazid
- ethambutol
- ethionamide
- delamanid
What drug has DNA synthesis mycobacteria target?
para amino salicylate
What drug has ATP synthase mycobacteria target?
bedaquiline
What are 3 shared mycobacterial targets?
- peptidoglycan-difficult so broadly B lactam resistant
- DNA dependent RNA polymerase
- protein synthesis (ribosome)
What drug has peptidoglycan mycobacterial target?
meropenem
What drug has DNA dependent RNA polymerase mycobacterial target?
rifampin and other rifamycins
What 5 drugs have protein synthesis mycobacterial targets?
- fluroquinolones
- aminoglycosides
- capreomycin
- linezolid
- macrolides
What are 2 types of mycobacteria?
- TB
2. environmental non-tuberculous mycobacteria (NTMs)
What is am exclusively pathogenic mycobacterai that can infect any human, and has no need for host susceptibility?
TB
What are drug targets for TB? (7)
- thick waxy cell wall
- DNA synthesis
- ATP synthase
- peptidoglycan
- DNA dependent RNA polymerase
- protein synthesis, ribosome
- unknown
Drugs that target thick waxy cell wall in TB? 5
isoniazid, ethambutol, ethionamide,
delamanid/pretomani
Drugs that target DNA synthesis in TB? 1
para amino salicylate
Drugs that target ATP synthase in TB? 1
bedaquiline
Drugs that target peptidoglycan in TB? 1
meropenem
Drugs that target DNA dependent RNA polymerase in TB? 1
rifampin, other rifamycins
Drugs that target protein synthesis, ribosome in TB? 4
fluoroquinolones, aminoglycosides,
capreomycin, linezolid
Drugs that have unknown targets in TB? 2
pyrazinamide, clofazimine
In drug resistant TB which two big drugs do you lose?
isoniazid and rifampin
Downside of drug resistant TB
Becomes increasingly difficult to develop an effective non-toxic regimen
Environmental non-tuberculous mycobacteria
NTM
NTM mainly infects (5)
susceptible patients, CF, COPD, Bronchiectasis, AIDS (rare now)
What is the duration of NTM treatment?
long, can be years or incurable
What drug is resistant of M. abscessus that makes this very difficult to treat
rifampin
Disadvantages of fungal targets? (3)
- difficult to get selectivity
- similarity mean few unique targets
- Resistance mechanisms to most agents known
Advantage of fungal targets?
Mostly pathogens of immuno-compromized
Fungal drug targets? (3)
- unique outer cell wall
- unique sterols in plasma membranes
- DNA synthesis
Drugs that target unique outer cell wall in fungus infections? 1
echinocandins
Drugs that target unique sterols in plasma membranes in fungal infections? 2
polyenes (target sterol), azoles
target unique synthetic enzyme
Drugs that target DNA synthesis in fungal infections? 1
5 fluorocytosine
Which type of fungal resistance do most species have?
intrinsic resistance to some or many classes of
drugs
Why do many species have intrinsic resistance?
most drugs being natural products, so many
fungi have ‘seen’ them before
