Fluroquinolones (MC) - Block 2

Question 1

What are the primary targets of quinolones?

Answer 1

G+: Topoisomerase IV
G-: DNA gyrase

Question 2

What is the function of DNA gyrase and topoisomerase IV?

Answer 2

DNA gyrase: removes/unwinding supercoils
Topoisomerase IV: removes/separation catenanes

Question 3

What is the cooperative bidnign model?

Answer 3

1. Drug binds to cleaved sDNA and traps enzymes
2. 4 quinolone molecules bind cooperatively to DNA via H-bonds to DNA bases
3. Quinolones stack forming pairs
4. Quinolones aggregate (1 and 8 positions)

Gyrase Tyr122 mutants can’t cleave DNA but can still bind to quinolones
* sDNA is not necessary for target

Question 4

What is the Mg2+ bridge model?

Answer 4

1. Drug binds to DNA phosphates -> chealation by Mg2+
2. Quinolone stacks onto bases
3. Quinolone indues conformational change in gyrase-DNA complex

Cleavage of DNA is not necessary for binding

Question 5

What is responsible of DNA segementation?

Answer 5

Tyrosyl

Question 6

Describe the activity of quinolones?

Answer 6

1. Bacteriocidal (concentration-dependent)

Question 7

ADR of quinolones?

Answer 7

1. Proconvulsant (N/V)
2. Joint erosion
3. Phototox
4. Tendon rupture
5. QT prolongation

Question 8

What causes resistance in quinolones?

Answer 8

1. Efflux mediated in G-
2. Mutation of target enzyme in G+

Question 9

What became a major structural component of quinolones?

Answer 9

1. F on C6
2. Piperizine at C7

Question 10

What are the med chem driveers for fluoroquin development?

Answer 10

1. Increase G+ coverage
2. Decreasing phototox
3. Improving F

Question 11

SAR of quinolones?

Answer 11

Question 12

How do quinolones get metabolized?

Answer 12

1. Cleaving the pipirizine ring -> inactivation
2. Phase 2 conjugation (glucoronide)
3. CYP1A2

Question 13

What is the pharmacophore of fluoroquines?

Answer 13

Piperazine ring

Question 14

Activity of quinolones IIa?

Answer 14

1. MRSA
2. Pneumococcus
3. Cipro -> P. aeruginosa

Question 15

Activitiy of IIIa

Answer 15

1. Pneumococcal
2. Balanced renal and hepato billiary elimination

Question 16

Activity of IIIb?

Answer 16

Pneumococcal (potent)

Question 17

What are your respiratory quinolones?

Answer 17

1. Ciprofloxacin
2. Levofloxacin
3. Moxifloxacin

Question 18

What quinolones tend to have the best activity?

Answer 18

1. Moxifloxacin
2. Gemifloxacn

Question 19

Descrie the PK of quinolones?

Answer 19

1. Zwitterionic -> decreased water solubility
2. CNS distribution (Fluror increases lipophillic) -> stimulation GABAa binding -> irritability
3. Derivatives are phototox
4. Chelation of metals can decrease absorption

Question 20

What is the best for P. aeuriginosa?

Answer 20

Ciprofloxacin

Question 21

What is used in CAP and nosocomial pneumonia?

Answer 21

Levaquin

Question 22

Describe the coverage of moxiloxacin?

Answer 22

1. Nonrenal clearance (hepato billiary system, no renal dose, CI in hepatic failure)
2. MDRSP

Question 23

Why was gatifloxacin removed from the market?

Answer 23

Hyperglycemia in diabetics
* available as eyedrops

Question 24

What is the most potent of quinolones?

Answer 24

Gemifloxacin
* no longer on the market

Question 25

How are most quinolone eliminatd?

Answer 25

renal (tubular secretion or glomerular filtration)

Question 26

Why are quinolone rarely used in children?

Answer 26

1. Growing cartilage -> arthropathy Used in children with pseudomonal infections with CF)

Question 27

What are the forms of quinolone resistance?

Answer 27

1. Mutation to parC gene that encodes for topoisomerase IV 2. Mutation to qyrA gene that encodes the A subunit of the type II topoisomerase DNA gyrase

Question 28

Describe types of resistance pertaining to efflux?

Answer 28

Mutations that inactivate a repressor of marA (decreases translation of ompF-porin protein) * Upreg of efflux, downreg of porins

Question 29

What is QNR?

Answer 29

1. Plasmid resist found in ESBL 2. Most common ABX resistance mechanisms * Encodes a 219 aa protein that binds to gyrase adn topoisomerase -> protects bacteria from drug binding