Lec2 Antibiotic Strategies Flashcards
What are the four main classes of antibiotics?
inhibitors of
- peptidoglycan [cell wall] synthesis
- protein synthesis
- polymerase activity
- folic acid metabolism
What are 4 main beta-lactam antibiotics that affect peptidoglycan synthesis?
- penicillin
- cephalosporin
- carbapenems
- monobactam
Where does penicillin come from?
- penicillium mold
Are gram + or - more affected by penicillin?
gram + because there is only one lipid bilayer to get through
How does penicillin work?
prevents synthesis of peptidoglycan cell wall by inhibiting transpeptidase that participates in cross-linking between parallel strands of murein
What is transpeptidase? Why is it significant?
an enzyme in bacterial cell wall that makes peptide cross-linking bonds to synthesize peptidoglycan
- it is inhibited by penicillin
What is significant in penicillin structure?
- contains beta-lactam ring = internal peptide bond
- contains two alanines within structure
- mimics substrate structure so feeds into transpeptidase active site and blocks it
What are 3 important beta lactams?
- penicillin
- cephalosporin
Cephamycin
What is beta-lactamase?
- enzyme that makes bacteria resistant to beta lactams [aka penicillin, cephamycin, cephalosporin]
- hydrolyzes the antibiotic beta-lactam structure
How do bacteria develop resistance?
via transposition of drug resistance genes and insertion of new sequences that code for nucleases so can cut the sequence to get circular segments of just the enzyme [penicilinase]
- the new r-determinant circular sequence that contains the enzyme can then be inserted into new plasmids to confer further drug resistance
What are two drugs that affect peptidoglycan synthesis?
vancomycin
bacitracin
What is mech of vancomycin?
recognizes ala and inhibits polymerization of peptidoglycan
What are two strategies of bacterial resistance to vancomycin?
strategy 1: decrease penetration of antibiotic to its target
strategy 2: alter target of antibiotic
What is significance of bacteria decreasing penetration of vancomycin?
- gram negative bacteria intrinsically resistant because vancomycin cannot get across outer membrane
What is mech of vancomysin resistance? which bacteria commonly have this?
- enterococci have plasma mediated resistance
- enzymes synthesize D-ala-D-lactic instead of D-ala-D-ala so vancomycin cannot recognize its target and will not prevent polymerization
What are 3 types of antibiotics that affect membrane of cell wall?
- polymyxins [cationic (+) detergents]
- polyene antibiotics [amphotericine B bind to sterols]
- azoles [inhibit cholesterol synthesis]
What is name for fungizone?
amphotericine B
What are 7 antibiotics that affect protein synthesis?
- aminoglycosides
- tetracyclins
- cholramphenicol
- macrolides [erythromycin]
- linezolid
- streptogramins
- clindamycin
What is mech of aminoglycoside action? What are the 3 mechs of resistance?
- affect protein synthesis
1. decreased penetration of antibiotic to target
2. alters target of antibiotic
3. inactivates antibiotic [MAIN MECH] by changing structure
What is mech of tetracyclin action? What is mech of resistance?
- affect protein synthesis
- transport of antibiotic out of cell
What is mech of chloramphenicol action? What is mech of resistance?
- affect protein synthesis
- by acetyl-transferase CAT
What is mech of macrolides [erythromycin] action? What is mech of resistance?
- affect protein synthesis
- alters 50s ribosomal proteins, methylation of 23s RNA
What is mech of linezolid action? What is mech of resistance?
- affect protein synthesis
- changes 23s RNA
What is mech of stretogramin action? What is mech of resistance?
- affect protein synthesis
- efflux, modifies/inactivates target
What is mech of clindamycin action? What is mech of resistance?
- affect protein synthesis
- methylation of 23s RNA
Which types of bacteria are intrinsically resistant to aminoglycosides? Why?
anaerobes and streptococci intrinsically resistant because active transport of aminoglycosides depends on e- transport chain
Which type of aminoglycosides can be resisted by altering target of antibiotic?
- streptomycin resistnace from 1 step mutation of 30s subunit
- newr aminoglycosides very rare to get resistance this way because require several mutations to get resistance
What is the most common resistance mech of aminoglycosides?
- inactivation of the antibiotic
- can be chromosome or plasmid mediated
- most common = plasmid mediated
- enzyme in bacteria DNA chemically modifies the antibiotic
Which type of aminoglycoside is hardest to inactivate?
- amikacin because it only has two sites that can be modified to inactivate
- thus bacteria that resistant to other aminoglycosides may still be affected by amikacin
What are 4 DNA-dependent DNA polymerase inhibitors?
- quinolones
- nalidixic acid
- mitomycin
- metronidazole
What is mech of quinolones?
- inhibits gyrase [cleave and allow twisting] and topoisomerase [unwinds DNA to make available to DNA polymerase]
- specifically inhibit bacterial enzymes not the human versions
What is mech of nalidixic acid?
- inhibits gyrase
What is mech of mitomycin?
- cross-links DNA [not very specific for bacteria vs our own DNA]
What is mech of metronidazole?
- damages DNA by free radicals causes DNA fragmentation
- not very specific for bacteria so can be very toxic
- activated mostly under anaerobic conditions
- imp for GI bacteria
What are 2 drugs that inhibit DNA-dependent RNA polymerase?
- rifampicin
- actinomycin D
What is mech of rifampicin action?
- binds to polymerase directly
- prevents initation complex of polymerase
What is mech of actinomycin D actin?
- intercalates DNA [slips between two strands of DNA so RNA polymerase can’t work]
What are two folic acid antimetabolites?
- sulfonamides
- trimethoprim
What is mech of sulfonamides?
- folic acid antimetabolite
- inhibits folic acid synthesis
What is mech of trimethoprim?
- folic acid antimetabolite
- inhibits reduction of folic acid to THF [tetrahydrofolic acid]
- produce more of enzy
What do folic acids do?
- needed for building of amino acids/proteins/DNA
- bacteria needs it to make its building blocks
What are two mech of trimethoprim resistance?
enzyme overproduction or resistant enzyme
What is mech of methicilin resistance?
loss of binding protein
What is synergy vs indifference vs antagonism?
synergy- A+B get lower level of bacteria than A or B alone
indifference- A+B is basically the same as A cause B doesn’t do much
antagonism- A alone works, A in presence of B has less of an effect
What is required for aminoglycosides to work? what does this mean for giving aminoglycoside + another protein synthesis inhibitor at same time?
- in order for aminoglycoside to work you need to have protein synthesis occuring because thats what it inhibits
- if you stop protein synthesis completely by giving another protein synthesis inhibitor at same time you get antagonism so not as good effect
What does isoniazid treat?
treats TB
What does pyrazinamide treat?
treats TB
What does ethambutol treat?
treats TB
What does pentamidine treat?
treats PCP pneumonia
What does zyvox do?
- protein synthesis inhibitor
- treats MRSA and vancomycin resistant strains
what does synercid do?
- protein synthesis inhibitor
- treats vancomycin resistant enterococcus
What does tygacil do?
- protein synthesis inhibitor
- treats MRSA
