Chemotherapy L6

Question 1

describe Intrinsic (natural) resistance

Answer 1

refers to inherent insensitivity to a drug

the drug just doesnt work - the organism may lack the target ect.

not aquired / developed.

Question 2

describe aquired resistance

Answer 2

refers to a situation where organisms that were originally sensitive to a drug, become less sensitive or insensitive to a drug

Question 3

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.

Answer 3

intrinsic resistance

Question 4

list 3 classes and exmaples of Biochemical mechanisms of bacterial drug resistance

Answer 4

I. Enzymatic inactivation of drugs.

II. Replacement, modification or amplification of drug targets.

III. Drug efflux, drug uptake

Question 5

describe the Hydrolysis of b-lactam antibiotics

Answer 5

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

Question 6

describe molecularly how B lactamases work?

Answer 6

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.

Question 7

how does class B B-Lactamases wokr

Answer 7

No covalently enzyme-drug interaction in Class B b-lactamase - throguh a zinc ion.

Question 8

why are class B lactamases a pain in the arse?

Answer 8

the failure of class B lactamases to be inhibited by class A, C and D lactamase inhibitors.

Question 9

describe how bacterial enzymes can modify antibiotics to make tehm redundant?

Answer 9

(aminoglycosides, chloramphenicol and others)

interfers with the recognition of the 16 S subunit fo the ribosome

Question 10

It is likely that these antibiotic inactivating enzymes have evolved from ___ ____ ____ that had been utilized for normal biosynthetic processes in the bacterial cells

Answer 10

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

Question 11

t or F

Analogous to the aminoglycoside- inactivating acetyltransferases are families of inactivating acetyltransferases for streptogramin, chloramphenicol, and others.

Answer 11

T

Question 12

can bacteria modify the target of antibiotics so theyre insensitive, but still retain their basic biochemical function?

Answer 12

yes

Question 13

describe methicillin

Answer 13

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

Question 14

describe how MRSA confers ressitance to Methicillin?

Answer 14

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

Question 15

MRSA poses a problem for treatment because it is resistant to……….

Therefore, b-lactam administration selects for MRSA in the clinical setting

Answer 15

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

Question 16

T o rF

MRSA is resistant to all b-lactam antibiotics

Answer 16

T

Question 17

T or F

MRSA is frequently also resistant to many non-β- lactam antibiotics

Answer 17

T

Question 18

what antibiotic was used to treat MRSA ?

Answer 18

Vancomycin

Question 19

what was the result of using vancomycin to treat MRSA?

Answer 19

• 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.

Question 20

describe: vancomyin resistance in Enterococcus faecalis (VRE)

Answer 20

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.

Question 21

describe how antibiotic resistance can occur because of reduced rug uptake

Answer 21

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.

Question 22

Aminoglycosides are often combined with a b-lactam drug in the treatment of S. aureus infections.

why?

Answer 22

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.

Question 23

describe drug efflux

Answer 23

Question 24

Active drug efflux can be clinically relevant for ….

Answer 24

Active drug efflux can be clinically relevant for b-lactam antibiotics, macrolides, fluoroquinolones, tetracyclines and many other drugs.

Question 25

driug efflux transported specificity?

Answer 25

Some efflux transporters are dedicated to a single drug or class of drugs, e.g. tetracycline transporters, whereas others exhibit an extremely broad drug specificity.

varies

Question 26

class of drug transport pumps?

Answer 26

Secondary active:

• Proton pump antiporter
• coupled proton pump antiporter

primary active transport:

• ATP dependant drug efflux

Question 27

Multiple drug resistance versus multidrug resistance

describe

Answer 27

The simultaneous expression of various antibiotic resistance mechanisms, each specific for a drug or class of drugs, gives rise to the phenomenon of multiple drug resistance.

drug efflux-based multidrug resistance. In this case the expression of a multidrug efflux pump in the plasma membrane confers resistance to a wide variety of drugs due to the enormously broad specificity of the pump

Question 28

Answer 28

Question 29

describe how resitance to the antifungal medication fluconazole works?

Answer 29

Antifungal azoles (e.g., fluconazole) inhibit enzymes involved in ergosterol biosynthesis;

azole resistance is based on alterations in the activity and amount of these enzymes, and on active azole efflux.

Question 30

describe how Resistance of herpesviruses to purine analogues (e.g., aciclovir) works?

Answer 30

Resistance of herpesviruses to purine analogues (e.g., aciclovir) is mostly based on a change in the substrate specificity of the viral purine-activating enzyme thymidine kinase, disabling the phosphorylation of purine analogues.

Question 31

Resistance to HIV reverse transcriptase inhibitors (e.g., zidovudine) or HIV protease inhibitors (e.g., saquinavir) is due to?

Answer 31

Resistance to HIV reverse transcriptase inhibitors (e.g., zidovudine) or HIV protease inhibitors (e.g., saquinavir) is due to mutations in these enzymes that disable the interaction between enzyme and inhibitor.

Question 32

Chloroquine-resistant parasites:

their resistance depends on

Answer 32

Chloroquine-resistant parasites accumulate chloroquine in their food vacuoles much less efficiently than chloroquine-sensitive strains, suggesting that drug resistance results mainly from exclusion of the drug from the site of action.

Originally it was thought that the lack of drug accumulation was the result of increased drug efflux from resistant parasites, and an ATP-dependent P- glycoprotein was implicated as the pump responsible. Although this notion is still supported by research, chloroquine efflux from the vacuole might be mediated by a mutated secondary-active transporter, termed CRT (chloroquine resistance transporter).

Question 33

give some ways cancer is resistant to chemotherapy

Answer 33

Question 34

how can we make antibiotics last longer?

Answer 34

not prescribe for viral infections

rotate their use in practice: 3 x 2month of each

limit the use in live stock as growth promoters

limit use of phrophylactic antibiotics

Question 35

in whayt ways can we improve existing drugs?

Answer 35

add new groups, alter characteristics and properties

Question 36

is it better to use combinations of drugs?

Answer 36

yess

Question 37

describe synergism?

Answer 37

Question 38

give some examples of combination therapy

Answer 38

Haart (highly active antiretroviral therapy) = saquinavir plus AZT plus nevirapine

Co-trimoxazole = antibacterial (sulfamethoxazole + trimethoprim)

Fansidar = antiplasmodial (sulfadoxin + pyrimethamine)

Artemisinin combination therapy (artemisinin + primaquine)

Question 39

give an exmaple of new antibiotic?

Answer 39

New compounds are also identified: for example teixobactin produced by the bacterium Eleftheria terrae binds to Lipid II and inhibits peptidoglycan synthesis.

Lipid targets are less prone to mutations = good targets

Question 40

how can we revive old antibiotics?

Answer 40

find new drugs to inhibit the resistance mechanisms

Question 41

read the notes last chapter 7 for more detail. im tired

Answer 41

nice

Question 42

fat

Answer 42

mamba