Antimicrobial chemotherapy Flashcards
Who else uses antibiotics (outside of humans) - to what percentage ? Purpose?
75% is animals
Some in plants
Prevents and treats disease & promotes growth
4 top disease causing mortality in the US in the 1900?
Pneumonia, TB, diarrhea & enteritis, diptheria
Why are microbials still important today?
Lower respiratory disease dna GI disease (diarrheal) are still hevay burdens - in top 10 leading causes of deaths
Where did the development of antibiotics start?
With penicillin (mold, fleming)
Later isolated by Florey and Chain
First use in Boston after a major fire (prevention of skin infections)
What was the secondary discovery of antibiotics? How
Streptomycin - systematicall discovered by Waksman by screening 10,000 strains of soial bacteria and fungi for antibacterial activity
What was the idea behind antibiotic usage?
That microbes have been continuously fighting one another in natural environments for over 40 million years
Where do most antibiotic classes originate from?
Natural compounds
What is the general concept between antibiotic action? for both types
bacteriostatic: interferes with a process allowing for microbe replication
bactericidal: interference in a process required for cell survival
process = reaction
-cidal vs -static activity?
killing vs growth inhibition (not an absolute distinction due to the variance within killing effects)
What is MIC? How do you determine it?
Minimal inhibitory concentraion: minimal concentration of a drug that inhibits growth of a particular organism
HIGH MIC = resistant
multiple different methods: most measure the zone of growth inhibition, or the dilution of drug that inhibits visible growth
Used to define whether a fungus/bacteria strain is resistant or not to a particular agent
What is AST? Use and limitations?
Antibiotic susceptibility testing = key diagnostic test in clinical microbiology to determine antibiotic susceptibility and identify resistance in bacterial pathogens causing infections
MIC thresholds are used to determine resistance vs susceptibility for each bacterial specie x drug combo
Cons:
require culture from pure bacterial colonies - cant be done directly on clinical samples
labour intensive and slow
What are the four major determinants for mechanisms of action of microbials?
-target
-spectrum of activity (gram positive or negative)
-bacteriostatic or cidal
-resistance of the microbe
What does the chemical structure of an antimicrobial determine?
-synthetic / semi-synthetic / natural product
-delivery type (oral vs injected vs topical)
-side effects
What do antibiotics target? (broad answer + three categories of antibiotics w/ target)
Essential cellular function and structures (conserved across bacterial species
-quinolones (RNA pol)
-beta lactams (cell wall)
-aminoglycosides macrolides (protein synthesis)
What are PBPs?
transpeptidase involved in cell wall bionsynthesis - equires D-alanyl-Dalanine to bind to
Properties of beta-lactam? (mechanism, example, limitation)
Penicilling!
Common beta-lactam ring
cell wall synthesis inhibitor
mimics D-Ala-D-Ala component of peptidoglycans - inhibit binding of PBP (penicillin binding proteins) disrupting cell wall synthesis (death by bursting due to osmotic pressure)
Wide spectrum with limited side effects
Generally cannot act on gram negatives (cant penetrate outer membrane)
Ribosome composition: prokaryotes vs eukaryotes?
Prokaryotes: 70S ribosome = 30S small, 50S large
Eukaryotes: 80S ribosome = 40S small, 60S large
How do antibiotics select for microbes with protein synthesis pathways?
Select for prokaryotes to limit side effects
Major protein synthesis inhibitors?
30S : tetracycline + aminoglycosides
50S: macrolides
Aminoglycosides processes and properties?
Bind to 30S ribosomal subunit - bactericidal
Broad spectrum for gram positive and gram negative, inactive againts obligate anaerobes
Important side effects
How does one choose an antibiotic?
-Spectrum
-Mode of delivery
-Dosing
-Antibiotic resistance
-Clinical indication (valid medical reason for a specific treatment or procedure for a condition)
-Clinical efficacy (clinical studies, microbiology potency, pharmacokinetic)
-Side effects and toxicity
-Cost and availability
Cons of antibiotic usage?
Profound disturbances to the microbiota
Short term effects (fungus and yeast overgrowth)
Antibiotic resistance
Unknown long term effects
What is happening to antibiotic resistance?
Increasing, increasing mortality, health cost and antibiotic resistant infections (1/4)
Threatens a century’s worth of progress in health and sustainability
What does a post antibiotic era entail?
End to modern medicine as we know it - things as common as strep and a skinned knee could kill us, with replacement therapy costing more and requiring a much longer treatment
Where is antibiotic resistance predicted to become an issue in 2050? Where is it already an issue?
2021: Africa, southwest asia
2050: North, south and West asia (east too), africa, south america
What is antibiotic resistance?
Ability for bacteria to grow in the presence of antibiotics
Generally mediated by mutations or resistance genes
Defined by high MIC (minimal inhibitory concentration)
What is a disc diffusion assay? What happens to it when microbes have antibiotic resistance?
paper disks with known amount of antimicrobial on agar plate inoculated with bacteria
antimicrobial diffuses into the agar - inhibits bacterial growth
creates inhibition zone. -> size = the level of resistance.
small zone of inhibition = resistance
Where did antibiotic resistance originate from?
Resistance mechanisms have evolved from competition and survival in countless numbers of bacterial species in the natural environment
Natural process
accelerated by human behaviour and environment
Two categories of antibiotic resistance origination?
-Lucky, advantageous mutation
-Expropriating genes (kidnapping resistance mechanisms, enzymes or plasmids)
How does antibiotic resistance spread within a bacterial population?
-Vertical gene transfer (one generation to another)
-Horizontal gene transfer (transfer of resistance genes from one bacteria to another
List of mechanisms of antibiotic resistance?
-Impaired influx
-Efflux
-Target mutation
-Target modification
-Overproduction of target mimic
-Factor association protection
-Drug modification
-Drug degradation
Explain antibiotic resistance due to impaired influx?
Gram (-): outer membrane + cell wall are highly impermeable and act as a selective barrier
Intrinsic resistance, as antibiotic must enter through size-limited pores
Explain antibiotic resistance due to efflux
Antibiotics are pumped out of the cell and cannot reach targets (gram (-) bacteria)
Uses complex multi purpose efflux pumps
Can cause multi-drug resistance
Explain antibiotic resistance due to target modification or mutation?
Genetic mutation, enzymatic modification or aquisition of a variant target with low affinity to antibiotic
Explain antibiotic resistance due to drug modification or degradation?
Degradation of beta-lactam by beta-lactamase
Inactivation of aminoglycosides by addition of groups by transferases (prevents binding of 30S subunit)
How does human behaviour promote antibiotic resistance?
-Antibiotic overuse (in agriculture + minor bacterial infections)
-Antibiotic misuse (improper use - wrong diagnosis, insufficient treatment length)
How to find new antibiotics?
Improve existing compounds
Natural products
Synthetic compounds
New targets
Unknown targets but known drugs
