Synthetic Antimicrobial Agents

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?

Sulfamethoxazole

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 false 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

Trimethoprim (Primsol) MOA

Bacteriostatic or bacteriocidal?

MOA?

Spectrum

Resistance?

Answer 8

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

Question 9

Mode of action of Trimethoprim

Answer 9

Question 10

Clinical Uses of trimethoprim-sulfamethoxazole

Primary uses

Toxicity?

Resistance?

Answer 10

Combination used to reduce resistance

Static + Static = Cidal

Question 11

Synergistic Combo of antifolates blocks?

Whole mechanism

Answer 11

Question 12

Treating UTIs

Answer 12

Question 13

Fluoroquinolones

General structure

Common use

Potency and spectrum

Use will become?

Answer 13

Question 19

Spectrum and SAR for Common FQs

Cipro, Levo, Moxi

Answer 19

Question 20

Adverse Rxns and SAR for common FQs

Answer 20

Question 21

FQs classification by Generations and AEs

Answer 21

Question 22

Nitrofurantoin

Orally active for the treatment of?

Little?

Acute SEs?

_____ groups are rarely found in drugs due to?

Answer 22

• 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 23

Metronidazole (flagyl)

Classic agents used against?

Increasing use against?

MOA?

Answer 23

• 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 24

Methenamine

Static or cidal?

Spectrum?

Resistance?

Cons?

Old

Used for?

MOA?

What is required for this drug to work?

Answer 24

• 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

Question 26

What enzyme do fluoroquinolones act on?

Inhibition at this site leads to?

Answer 26

• 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 27

Catalytic Cycle of DNA Gyrase Cleavage of DNA

And Effect of FQs

Answer 27

• 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 28

FQs are bacteriostatic or cidal?

Answer 28

Cidal

Question 29

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

Answer 29

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

Question 30

FQs Toxicity and Resistance

Resistance is?

Toxicity varies but include?

Answer 30

• 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 31

Synergistic Effects of Sulfonamides and Trimethoprim What is special about getting resistance to this?

Answer 31

* Resistance needs mutations to two distinct enzymes * Less likely to have resistance * MO that is already resistant to one component can easily gain resistance to the other * Metabolic bypass possible (Strepto and Enterococci)

Question 32

Topoisomerases ____ the state of DNA supercoil Critical for? Inhibition can lead to? FQs: Bacterial? DNA gyrase? TOPO IV?

Answer 32

* Change * DNA and protein synthesis (S and G2) * Inhibition can lead to DNA cleavage and apoptosis * topo II * Gram (-) * Gram(+)

Question 33

\_\_ ions mediate quinolone interactions with?

Answer 33

Question 34

Less frequently used quinolones 3

Answer 34