Synthetic Antimicrobial Agents Flashcards
TMP is a competitive inhibitor of?
This causes?
DHFR-
This inhibits the reduction of folate for DNA synthesis
SMX inhibits?
Sulfamethoxazole
- Inhibits the reduction of folate.
Folic acid biosynthesis as a target for antibacterial drugs
3 things
- Humans do no biosynthesize folic acid and get it from their diet
- Susceptible bacteria unable to abosorb folic acid must make their own from component parts
- Inhibition of folic acid biosynth will cease DNA biosynth in bacteria
Sulfa drugs bind to ____ causing a ____ metabolite which?
- dihydropteroate diphosphate
- Making a false metabolite
- Inhibits the synthesis of new bacteria DNA
Where are the 2 spots sulfa drugs inhibit DNA synth?
- Binds to dihydropteroate diphosphate making a false metabolite
- Block dihydropteroate synthase
MOA of sulfa drug
- Incorporation of sulfanamides generates a false metabolite that can not convert to THFA
- Sulfonamides function as an antimetabolite of PABA to block dihydropteroate synthase, which inhibits conversion of dihydropteroate to DHPA
How can bacteria be resistant to sulfa drugs?
- Metabolic bypass is the biggest factor (Streptococcus and Enterococcus) both take up folate from the host.
Trimethoprim (Primsol) MOA
Bacteriostatic or bacteriocidal?
MOA?
Spectrum
Resistance?
- 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
Mode of action of Trimethoprim
Clinical Uses of trimethoprim-sulfamethoxazole
Primary uses
Toxicity?
Resistance?
Combination used to reduce resistance
Static + Static = Cidal
Synergistic Combo of antifolates blocks?
Whole mechanism
Treating UTIs
Fluoroquinolones
General structure
Common use
Potency and spectrum
Use will become?
Spectrum and SAR for Common FQs
Cipro, Levo, Moxi
Adverse Rxns and SAR for common FQs
FQs classification by Generations and AEs
Nitrofurantoin
Orally active for the treatment of?
Little?
Acute SEs?
_____ groups are rarely found in drugs due to?
- 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
Metronidazole (flagyl)
Classic agents used against?
Increasing use against?
MOA?
- 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
Methenamine
Static or cidal?
Spectrum?
Resistance?
Cons?
Old
Used for?
MOA?
What is required for this drug to work?
- 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
What enzyme do fluoroquinolones act on?
Inhibition at this site leads to?
- 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
Catalytic Cycle of DNA Gyrase Cleavage of DNA
And Effect of FQs
- 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
FQs are bacteriostatic or cidal?
Cidal
Floxacin FQs all contain a ____ pharmacophore that can pose problems if someone is taking ____ due to decreased ___
- Beta-keto acid pharmacophore
- Suppliments with metal or MV because these metal ions bind to the pharmacophore and decrease its bioavailability
FQs Toxicity and Resistance
Resistance is?
Toxicity varies but include?
- 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
Synergistic Effects of Sulfonamides and Trimethoprim
What is special about getting resistance to this?
- 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)
Topoisomerases ____ the state of DNA supercoil
Critical for?
Inhibition can lead to?
FQs: Bacterial?
DNA gyrase?
TOPO IV?
- Change
- DNA and protein synthesis (S and G2)
- Inhibition can lead to DNA cleavage and apoptosis
- topo II
- Gram (-)
- Gram(+)
__ ions mediate quinolone interactions with?
Less frequently used quinolones
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