Antimicrobial Chemotherapy, Fluoroquinolones

Question 1

TMP is a competitive inhibitor of?

This causes?

Answer 1

DHFR-

This inhibits the reduction of folate for DNA synthesis

Question 2

SMX inhibits?

Answer 2

• Inhibits the reduction of folate.

Question 3

Folic acid biosynthesis as a target for antibacterial drugs

3 things

Answer 3

1. Humans do no biosynthesize folic acid and get it from their diet
2. Susceptible bacteria unable to abosorb folic acid must make their own from component parts
3. Inhibition of folic acid biosynth will cease DNA biosynth in bacteria

Question 4

Sulfa drugs bind to ____ causing a ____ metabolite which?

Answer 4

• dihydropteroate diphosphate
• Making a alse metabolite
• Inhibits the synthesis of new bacteria DNA

Question 5

Where are the 2 spots sulfa drugs inhibit DNA synth?

Answer 5

1. Binds to dihydropteroate diphosphate making a false metabolite
2. Block dihydropteroate synthase

Question 6

MOA of sulfa drug

Answer 6

1. Incorporation of sulfanamides generates a false metabolite that can not convert to THFA
2. Sulfonamides function as an antimetabolite of PABA to block dihydropteroate synthase, which inhibits conversion of dihydropteroate to DHPA

Question 7

How can bacteria be resistant to sulfa drugs?

Answer 7

• Metabolic bypass is the biggest factor (Streptococcus and Enterococcus) both take up folate from the host.

Question 8

Inhibition of ____ biosynthesis is ___ to the cell

Biosythn of ___ requires conversion of __–>__

____ is a necessary cofactor in? what pathway

Answer 8

• Inhibition of T biosynthesis is detrimental to the cell
• Biosythn of T requires conversion of U–>T
• THFA is a cofactor in
• PABA + DHPA —> DHFA –>THFA

Question 9

Trimethoprim (Primsol) MOA

Bacteriostatic or bacteriocidal?

MOA?

Spectrum

Resistance?

Answer 9

• Static
• Selective inhibition of bacterial DHFR —no T – no new DNA
• Target modification, altered DHFR, metabolic bypass as well
• Staph aureus, Poor activity with gram positive, mixed activity with gram negative

Question 10

Mode of action of Trimethoprim

Answer 10

Question 11

Clinical Uses of trimethoprim-sulfamethoxazole

Answer 11

Combination used to reduce resistance

Question 12

Synergistic Combo of antifolates blocks?

Whole mechanism

Answer 12

Question 13

Treating UTIs

Answer 13

Question 14

Fluoroquinolones

Answer 14

Question 15

Complications to Antimicrobial Therapy

3 of them

Answer 15

1. Biofilms
   
   1. EPS- interferes with antibiotics teaching target
2. Virulence Factors
   
   1. peptide like, interfere with immune response, and avoid, destroy, help bacteria cross membranes (Staph secretes PSMs evade immune response)
3. Post-infection Disease
   
   1. Inflammation continues after infection is gone causing tissue damage and disease

Question 16

What enzyme do fluoroquinolones act on?

Inhibition at this site leads to?

Answer 16

• Topoisomerase II
  
  • Called DNA Gyrase in Gram (-)
  • Topoisomerase IV in Gram (+)
• Inhibition can lead to DNA cleavage and apoptosis
• Basically keeps the DNA strand Cut

Question 17

Catalytic Cycle of DNA Gyrase Cleavage of DNA

And Effect of FQs

Answer 17

• The topo cuts the DNA
• FQs bind to the junction between topo and the cut DNA
• The ternary complex is locked in that the enzyme can not reseal DNA —> Bactericidal

Question 18

FQs are bacteriostatic or cidal?

Answer 18

Cidal

Question 19

Floxacin FQs all contain a ____ pharmacophore that can pose problems if someone is taking ____ due to decreased ___

Answer 19

• Beta-keto acid pharmacophore
• Suppliments with metal or MV because these metal ions bind to the pharmacophore and decrease its bioavailability

Question 20

FQs Toxicity and Resistance

Resistance is?

Toxicity varies but include?

Answer 20

• Is increasing
  
  • Single -step mutation to gyrA or gyrB confers low-level resistance
  • Mutations to both = major
  • Increased drug efflux and decrease in outer membrane permeability
• GI disorder, CNS, Photosensitivity or skin rash, tendinopathy, Glucose homeostasis
• Resistance+ Toxicity leads to minimal use and preferred for uncomplicated infections

Question 21

Spectrum and SAR for Common FQs

Cipro, Levo, Moxi

Answer 21

Question 22

Adverse Rxns and SAR for common FQs

Answer 22

Question 23

FQs classification by Generations and AEs

Answer 23

Question 24

Nitrofurantoin

Orally active for the treatment of?

Little?

Acute SEs?

_____ groups are rarely found in drugs due to?

Answer 24

• UTIs
• Resistance
• Pulmonary Rxns, neuropathy, anemia, hepatotoxic
• Pts have actually refused to take the drug due to the SEs
• Nitroaromatic groups are rarely found in drugs due to their toxicity

Question 25

Metronidazole (flagyl)

Classic agents used against?

Increasing use against?

MOA?

Answer 25

• Amoebal vaginitis
• Giardiasis, Gardnerella vaginalis and anaerobes (C. Difficile, C. Perfringens, Bacteroides)
• Antihelicobacter mixtures
• Involves the reduction of NO2 to generate radicals, not well understood

Question 26

Methenamine

Static or cidal?

Spectrum?

Resistance?

Cons?

Old

Used for?

MOA?

What is required for this drug to work?

Answer 26

• Cidal
• Broad spectrum
• low resistance
• Carcinogenic
• Hemorrhagic cystitis (hematuria (blood) with bladder pain)
• Used after other agents failed
• Reoccurring community acquired UTI
• Depolymerizes to generate formaldehyde and ammonia
• Need an acidic environment for drug to work so acidic drinks are suggested, orange juice