Chemotherapy L6 Flashcards
describe Intrinsic (natural) resistance
refers to inherent insensitivity to a drug
the drug just doesnt work - the organism may lack the target ect.
not aquired / developed.
describe aquired resistance
refers to a situation where organisms that were originally sensitive to a drug, become less sensitive or insensitive to a drug
what type of resistance?
Although fungal DNA-dependent RNA polymerase is inhibited by rifampin, this drug is not particularly effective against fungi because the drug does not readily pass through the fungal cell envelope to its site of action.
intrinsic resistance
list 3 classes and exmaples of Biochemical mechanisms of bacterial drug resistance
I. Enzymatic inactivation of drugs.
II. Replacement, modification or amplification of drug targets.
III. Drug efflux, drug uptake
describe the Hydrolysis of b-lactam antibiotics
B-lactamase opens up the B-lactam ring
B lactamase enzymes are very fast and very abundant in resitance bacteria.
ESBL = extended spectrum B lactamase
describe molecularly how B lactamases work?
essentially theyre modified transpeptidases (which the antibiotic inhibits)
but the actiae side is more open ,alloing water access - allows hydrolysis (class A, C, D)
inactivating the b lactam ring.
Clas A, C, D are all serine hydrolases.
how does class B B-Lactamases wokr
No covalently enzyme-drug interaction in Class B b-lactamase - throguh a zinc ion.
why are class B lactamases a pain in the arse?
the failure of class B lactamases to be inhibited by class A, C and D lactamase inhibitors.
describe how bacterial enzymes can modify antibiotics to make tehm redundant?
(aminoglycosides, chloramphenicol and others)
interfers with the recognition of the 16 S subunit fo the ribosome
It is likely that these antibiotic inactivating enzymes have evolved from ___ ____ ____ that had been utilized for normal biosynthetic processes in the bacterial cells
It is likely that these antibiotic inactivating enzymes have evolved from adenylyltransferases, phosphotransferases and N-acetyltransferases that had been utilized for normal biosynthetic processes in the bacterial cells.
since aminoglycosides are based on sugars and amino acids - theyre vulnerable to a whole plethora of existing side chain modifying enzymes
t or F
Analogous to the aminoglycoside- inactivating acetyltransferases are families of inactivating acetyltransferases for streptogramin, chloramphenicol, and others.
T
can bacteria modify the target of antibiotics so theyre insensitive, but still retain their basic biochemical function?
yes
describe methicillin
Methicillin is a β-lactam antibiotic that contains bulky 2,6 dimethoxy-benzoyl
substituent to circumvent b-lactamase activity
(increase in t1/2 of covalent drug-enzyme complex)
- first introduced in 1950
- effective strategy until MRSA developed:
1961 in Europe, 1980/90s globally
describe how MRSA confers ressitance to Methicillin?
NOT thorugh upregualtion of an alternative B lactamase.
gene MecA encodes a different transpeptidase with reduced affinity for beta lactam antibiotics
Usual interpeptide crossbridge in staphylococcal PG contains an additional interpeptide between Lys-3 and D-Ala-4 (mixture of L-glycine, L-serine, L-alanine). The fem (Factors Essential for Methicilline resistance) gene products generate (Gly)5. This is a better substrate of MecA transpeptidase than the mixed interpeptide.
Gly5 is what confers the resistance. aka the mechanism of peptidoglycan linking has changed
MRSA poses a problem for treatment because it is resistant to……….
Therefore, b-lactam administration selects for MRSA in the clinical setting
MRSA poses a problem for treatment because it is resistant to essentially all b-lactam molecules, including penicillins, cephalosporins, carbapenems, and monobactams. Therefore, b-lactam administration selects for MRSA in the clinical setting
T o rF
MRSA is resistant to all b-lactam antibiotics
T
T or F
MRSA is frequently also resistant to many non-β- lactam antibiotics
T
what antibiotic was used to treat MRSA ?
Vancomycin
what was the result of using vancomycin to treat MRSA?
- The answer to MRSA was the use of vancomycin as a first line drug.
- The increasing use of vancomycin to treat infections caused by the gram-positive MRSA in the 1980s and 1990s selected for drug-resistant enterococci, less potent pathogens than staphylococci but opportunistic in the space vacated by other bacteria and in patients with compromised immune system.
- E. faecalis species account for about 90 to 95% of vancomycin-resistant clinical isolates.
describe: vancomyin resistance in Enterococcus faecalis (VRE)
Target modification:
recall vancomycin binds to terminal D-ala D-ala on the pentapeptide in peptidoglycan synthesis?
vancomycin S receptors detect it.
and swtich on genes:
VanH = pyruvate dehydrogenase that converts pyruvate into lactate
- *VanA** = D-Ala-D-lactate synthase
- *VanX** = peptidase that cleaves off D-Ala-D-Ala (hydrolase)
these alter the terminal 2 AA. leading to a 1000 fold decrease in affinity for vancomycin.
describe how antibiotic resistance can occur because of reduced rug uptake
Aminoglycoside resistance in Pseudomonas aeruginosa is obtained by mutations in outer membrane porins and active uptake systems in the cytoplasmic membrane (for oligopeptides?)
aminoglycosides use sugar transporters usually. so cant enter the bacteria
decrease in the number of porins
and also by modifications to the lipopolysaccharide outer leaflet, which further reduces passive influx.
Aminoglycosides are often combined with a b-lactam drug in the treatment of S. aureus infections.
why?
The b-lactam drug affects cell wall synthesis and increases the passive diffusion of the aminoglycoside into the cell.
This combination therefore enhances bactericidal activity, whereas aminoglycoside monotherapy may allow resistant staphylococci to persist during therapy and cause a clinical relapse once the antibiotic is discontinued.
describe drug efflux
Active drug efflux can be clinically relevant for ….
Active drug efflux can be clinically relevant for b-lactam antibiotics, macrolides, fluoroquinolones, tetracyclines and many other drugs.
