Mechanisms of Drug Action Final Exam

antibiotics

substances produced by various species of microorganisms that suppress the growth of other microorganisms and eventually may destroy them

bacteriostatic

useful when host defenses are maximally effective, inhibits further growth of bacterial colonies - does not kill present colonies

bactericidal

necessary when host defenses are impaired, destroys and kills any future colonies

what makes an organism susceptible to antibiotics?

if the dose of the drug is high enough to inhibit or kill the invading organism but low enough to avoid harming the host

what makes a drug resistant to antibiotics?

if the dose of a drug needed to inhibit or kill the invading organism is toxic to the host

what is the conjugation mechanism of gene transfer?

transfer of DNA due to physical contact between 2 bacteria via pilus projection

what is the transduction mechanism of gene transfer?

a virus transfers DNA from the bacteriophage to the bacterium

what is the transformation mechanism of gene transfer?

the bacteria uptakes free DNA from the environment

what is the alteration of target site mechanism for antibiotic resistance?

the target site for the antibiotic is altered and it can no longer bind, leading to no effect

what is the enzymatic degradation mechanism of antibiotic resistance?

the antibiotic can enter the cell, but bacterial enzymes degrade/alter the antibiotic stopping the effect

what is the bypass pathway mechanism of antibiotic resistance?

the antibiotic is supposed to inhibit a particular step in the pathway, the bacteria develops a way to go around this step and continue

what is the efflux pump mechanism of antibiotic resistance?

protein based transporters can remove antibiotics from within the bacterial cell not allowing for accumulation of antibiotics

what is the decreased entry mechanism of antibiotics resistance?

reduces the entry of antibiotics into the cell by modifying the outer membrane porins not allowing for penetration

why might an antibiotic not be able to reach the target site?

the bacterial cell membrane is impermeable, pH not conducive to drug influx, the mechanism for transport of the drug is energy dependent and inactive in anaerobic environments

why might an antibiotic become inactivated?

it could be due to enzymes present at or within the cell surface

why might the target site of an antibiotic be altered?

it could be due to natural variation or propagation of a mutant strain

how do penicillin and aminoglycosides work together as combined antibiotic therapy?

aminoglycoside is a protein synthesis inhibitor but cannot enter the cell, penicillin can breakdown/inhibit the cell wall allowing for aminoglycoside to enter and kill the cells

what are reasons for using combined antibiotic therapy?

prevent emergence of resistant bacteria, treat a polymicrobial infection, permit the use of a lower dose of antimicrobial agents, to achieve synergy, empiric therapy when infecting pathogen is unknown,

how are antibiotics misused?

used to try and treat viral infections, improper dosage, reliance on chemotherapy alone, lack of adequate knowledge

gram positive bacteria have what?

thick layers of peptidoglycan, an outer layer outside the cell membrane

gram negative bacteria have what?

lipid outer membranes with thinner layers of peptidoglycan

both gram positive and negative membranes contain?

beta - lactamase enzymes (cleave penicillin and other lactamase to make them inactive) and penicillin binding proteins (take short peptide strands and link them together to increase membrane rigidity

peptidoglycans

crosslinked strands made up of NAM and NAG monomers connected by B-1,4 linkages

how do the peptidoglycans become crosslinked?

penicillin binding protein attaches to the terminal alanyl-alanine, cleaves the 5th nucleotide (alanine) and attaches to the 4th peptide to the neighboring peptide

beta-lactams (penicillin) are bacterio? and what is the mode of action?

-cidal, structure mimics the alanyl-alanine and competes out the binding proteins (antagonist), peptidoglycans have less ability to cross link weaking the cell wall

beta-lactamase inhibitors

work together, inhibit b-lactamase enzymes and targets PBPs - protecting antibiotics containing lactam rings from degradation

what are carbapenems?

antibiotics that are resistant to b-lactamase degradation due to their R-group

b-lactam/b-lactamase inhibitor combinations

amoxicillin/clavulanate, ticarcillin/clavulanate, ampicillin/sulbactam, piperacillin/tazobactam

vancomycin and bacitracin are bacterio? and work how

-cidial, target the terminal alanyl alanine of cell wall precursor units, associate very tightly and prevent binding of penicillin binding protein leading to a reduction in cell wall crosslinking

vancomycin is typically reserved for

resistant infections like MRSA

what is the general mechanism of prokaryotic protein synthesis

30S and 50S come together and form ribosome complex around mRNA, methionine starts the process and comes in as charged tRNA, moves down mRNA, switch of positions from A site to P site, next charged tRNA comes in, reaction forms peptide bond linking the amino acids together, old tRNA removed and chain continues

which of the prokaryotic ribosome subunits contain the enzymatic activity?

50S

what are examples of aminoglycosides?

gentamicin, kanamycin, tobramycin, neomycin, streptomycin, amikacin

aminoglycosides are bacterio? and how do they work?

-cidial (some created proteins create weak cell membrane and lead to leakage of contents), they bind to the 30S subunit blocking assembly of initiation complex, leads to misreading of mRNA and premature termination, blocks movement of the ribosome

tetracyclines

doxycycline, bind to the 30S subunit, contain 4 rings, prevent access of the aminoacyl tRNA to the acceptor site - no elongation and premature termination

chloramphenicol

binds to the 50S subunit, prevents the binding of the amino acid on the aminoacyl tRNA to the 50S subunit, the tRNA CAN come into the A site but the amino acid does not, cannot form peptide bonds

why is chloramphenicol only used to treat serious diseases (what are they)?

also inhibits host mitochondrial protein synthesis, leads to serious side effects - treats meningitis, typhus, and rocky mountain fever

what are examples of macrolides?

erythromycin, clarithromycin, azithromycin

how do macrolides work?

inhibit the translocation of the growing peptide and tRNA from A site to the P site leading to premature chain termination

what is tetrahydrofolate (folic) acid?

used in the production of nucleotides and amino acids, source of carbons that make up the rings of purines (adenine and guanine), bacteria synthesize their own folic acids

what is PABA?

para amino benzoic acid - important part of the first step in folic acid synthesis

examples of sulfanilamides

sulfadiazine, sulfisoxazole, sulfamethoxazole, sulfathalidine

how do sulfanilamides work, they are bacterio?

inhibits the first step in folic acid synthesis (dyhydropteroate synthase), -static effective during replication but not on current live cells

what are the positives and negatives of sulfonamides?

do not cause effect on host cells (humans get folic acid from their diet), contain a sulfur group, some can have an allergy and lead to anaphylaxis

trimethoprim

also inhibits the production of folic acid by inhibiting the end of synthesis via dihydrofolate to THF

how do sulfonamides and trimethoprim create synergy?

if sulfonamides inhibit 50% of the first step and trimethoprim inhibits the other 50% no folic acid can be created and no nucleotides for amino acids are synthesized

what are bacterial resistance mechanisms to sulfonamides

alterations in dihydropteroate synthase, increased capacity to destroy drug, alternative metabolic pathway, increased synthesis of PABA

what is the mechanism for bacterial DNA replication?

plasmid has double stranded circular DNA that needs to be separated to make a replication bubble, supercoiling occurs at the corners of the bubble, DNA gyrase cuts one of the strands and allows for strand to pass through, DNA polymerase can attach to leading strand and replicate strand, DNA ligase comes through and repairs cuts

fluroquinolones

inhibit bacterial DNA replication by inhibiting DNA gyrase - good alternative therapy for someone allergic to sulfonimides

different types of tinea fungus infections

athletes foot, nail infection, ring worm

what is the key difference between fungi and mammalian cells

very similar in structure which can lead to issues with drugs attacking the host cells but fungi have an external cell wall before the cell membrane, key is to target this instead

fungal cells contain what that is similar to cholesterol

ergosterol

amphotericin B

top branch is hydrophilic, bottom is hydrophobic - hydrophobic side interacts with ergosterol in the cell membrane while the hydrophilic side aligns the opposite way creating channel out of the membrane - the cell is now leaking contents out of the membrane leading to death

terbinafine and tolnaftate

inhibit squalene epoxidase in ergosterol synthesis, inhibiting synthesis of ergosterol will destabilize the membrane

imidazoles and triazoles

-azoles, inhibit the synthesis of ergosterol at a later step by stopping 14-alpha-demethylase - reduces ergosterol but also increases abundance of toxic intermediates which then insert into the membrane and increase membrane permeability and function of membrane enzymes

flucytosine (5-FC)

analogue of cytosine, gets acted on to create a fluorouracil that then gets incorporated into RNA causing miscoding of proteins and premature chain termination - 5-FU also inhibits thymidylate synthase (thymidine - T) which inhibits DNA synthesis

echinocandins

fungicidal, weaken cell wall and cause lysing - B-1,3 glucan synthase inhibitors

what are examples of echinocandins

caspofungin, micafungin, anidulafungin

when are echinocandins given, why are they good, why arent they used often

they are given for infections that arent susceptible to other treatments or immunocompromised patients, tend to have less side effects, but they are not cost effective and expensive