IID 11: Chemistry of AMG/FQ/TMPSMX/Misc Flashcards
Chemistry of Aminoglycosides
Describe the structural components of aminoglycosides.
amino sugar building blocks
- contains 1,3-diaminoinositol moiety attached through glycosidic bonds to other amino sugars to form pseudo-oligosaccharides
Chemistry of Aminoglycosides
List physicochemical properties of aminoglycosides that impact ADME processes.
- basic (form acid salts)
- water-soluble
- upon oral administration, they are confined to GI tract
- after injection, they are excreted in urine
Chemistry of Aminoglycosides
Describe the mechanism of action of aminoglycosides toward inhibiting protein synthesis.
- aminoglycosides bind initially to external lipopolysaccharides and diffuse into cells in small amounts – this uptake is inhibited by Ca2+ and Mg2+ ions, which are therapeutically incompatible with this drug class
- aminoglycosides bind to 16S rRNA of 30S ribosomal subunit, impairing the proofreading function of the ribosome at the A site (conformational change) and promoting the formation of nonsense proteins
- nonsense proteins are involved in upsetting
bacterial membrane function – the compromised membrane then allows for more antibiotic to enter the cell - binding is largely comprised of H-bonding between the phosphate backbone of 16S rRNA and the aminoglycoside
Chemistry of Aminoglycosides
List the different ways in which bacteria can become resistant to aminoglycosides.
- R-factor-mediated enzymes modify amino and hydroxyl groups
- decreased active uptake into cells
- point mutations in ribosomal A site
- ie. HABA group in amikacin inhibits distal sugar modifications, enhancing potency and spectrum
(the fewer sites available for modification, the broader the spectrum and higher the potency)
Chemistry of Aminoglycosides
Explain the structural features of aminoglycosides that affect bacterial resistance mechanisms (primarily R-factor-mediated enzymes) and how the spectrum of activity can be impacted.
– see notes
Chemistry of Fluoroquinolones
What is topoisomerase II (DNA gyrase)?
ATP-dependent enzyme that introduces negative supercoils in positively supercoiled DNA to:
- release tension
- provide accessibility for transcription and replication
(important target in some gram-negative bacteria)
Chemistry of Fluoroquinolones
What is topoisomerase IV?
ATP-dependent enzyme that:
- decatenates DNA after replication
- releases tension in positively supercoiled DNA similar to DNA gyrase
(important target in some gram-positive bacteria)
Chemistry of Fluoroquinolones
What does inhibition of topoisomerase II (DNA gyrase) or topoisomerase IV do?
makes a cell’s DNA inaccessible and causes cell death
Chemistry of Fluoroquinolones
Explain how human DNA shaping (ie. supercoiling and decatenating) is not affected by fluoroquinolones.
– see above
Chemistry of Fluoroquinolones
Describe the structure of quinolone antimicrobials.
comprise a group of synthetic substances possessing an N-1-alkylated 3-carboxypyrid-4-one ring fused to another aromatic ring bearing additional substituents
Chemistry of Fluoroquinolones
What two quinolones were of little clinical significance and why?
nalidixic acid and cinoxacin
- had too narrow of a spectrum of activity toward a small number of gram-negative bacteria
Chemistry of Fluoroquinolones
What are quinolones (including fluoroquinolones) incompatible with?
polyvalent metal ions
- co-administration results in decreased solubility and reduced drug absorption
- agents containing polyvalent metals should be administered at least 4 h before or 2 h after quinolone dosing
Chemistry of Fluoroquinolones
Explain the chemical and functional differences between quinolones and fluoroquinolones (FQs).
–
Chemistry of Fluoroquinolones
Explain the four major structure-activity relationship features of 4-quinolones.
- (substitution at C-2 interferes with enzyme:inhibitor complex)
- (reduction of 2,3 double bond or 4-keto group inactivates drug)
- cyclopropyl/alkyl group at N-1 broadens activity spectrum toward Gram-positive bacteria (ie. S. aureus)
- fluorine atom at C-6 increases lipophilicity, which improves cell wall penetration, drug absorption, and half-life, and increases enzyme inhibition activity – however, a fluorine atom at C-6 increases photosensitivity
- methoxy/alkoxy group at C-8 reduces photosensitivity
- heterocyclic substitution at C-7 improves the spectrum of activity against Gram-negative bacteria, and improves oral absorption, tissue distribution, and metabolic stability
Chemistry of Fluoroquinolones
What are some 2nd generation fluoroquinolones?
- norfloxacin
- ciprofloxacin
- ofloxacin
Chemistry of Fluoroquinolones
Norfloxacin and Cirpofloxacin (2nd Generation)
piperazine at C-7 makes drug zwitterionic, resulting in Gram-negative spectrum and ADME improvements – however, it also
increases antagonistic binding to CNS GABA_A receptors
Chemistry of Fluoroquinolones
Ofloxacin (2nd Generation)
- alkylation of piperazyl group reduces GABA_A receptor binding
- alkoxy group at C-8 fused to a cyclopropyl isostere with an asymmetric carbon
Chemistry of Fluoroquinolones
What are some 3rd generation fluoroquinolones?
- levofloxacin
Chemistry of Fluoroquinolones
Levofloxacin (3rd Generation)
S-(-) isomer is 2x more active than ofloxacin & 128x more potent than R-(+) isomer
Chemistry of Fluoroquinolones
What are some 4th generation fluoroquinolones?
- moxifloxacin
- gatifloxacin
- gemifloxacin
Chemistry of Fluoroquinolones
What is the mechanism of action of fluoroquinolones?
- form a ternary complex with the enzyme and bound DNA just before the crossover stage of topoisomerase activity
- complex is stable, so the cut DNA strands are not resealed
- human cells do contain topoisomerase enzymes, but fluoroquinolones exhibit a roughly 1000x selectivity for the bacterial enzyme over the corresponding human enzyme
Chemistry of Sulfonamides
Describe how sulfonamides can affect the microbial biosynthetic pathway of tetrahydrofolic acid synthesis (ie. compete with p-amino benzoic acid (PABA) for dihydropteroate synthase or generate a false metabolite).
- bacteria synthesize their own folic acid, whereas humans rely on dietary sources
- competitive inhibition
- sulfanilamide incorporation
- see notes
Chemistry of Sulfonamides
Describe the key structural similarities and differences between sulfanilamide and PABA.
- sulfanilamide: SO2NH2 group
- PABA: COOH group
Chemistry of Sulfonamides
Show mechanistically how decreasing the pKa of sulfonamides improves solubility and reduces toxicity.
- poor water solubility of early sulfonamides led to occasional crystallization in the urine (crystalluria) and resulted in kidney damage because the molecules were not ionized at physiological pH
- attaching an EWG (ie. isoxazole) to the nitrogen decreases the pKa by stabilizing the conjugate base in order to prevent crystalluria – potency improves with a lowered pK a as well
Chemistry of Sulfonamides
What are the 3 clinically relevant sulfonamides and their structure and pKa’s?
- sulfadiazine: pkA = 6.5
- sulfamethoxazole: pkA = 5.6
- sulfisoxazole: pkA = 5.0
Chemistry of Sulfonamides
What are some mechanisms of resistance toward sulfonamides?
- plasmid-mediated mechanisms commonly found in Gram negative bacteria include decreased dihydropteroic acid synthase sensitivity to sulfonamides (reduced binding), and increased p-ABA production
- efflux pumps
Chemistry of Sulfonamides
What is the mechanism of resistance toward sulfonamides that trimethoprim mitigates?
- bacterial cells that take up folic acid no longer require the activity of dihydropteroic acid synthase to make thymidine, just the activity of dihydrofolate reductase to reduce dietary folic acid partially to DHF, and then fully to THF
Chemistry of Sulfonamides
What is trimethoprim (TMP)?
antifolate competitive inhibitor of the dihydrofolate reductase (DHFR) enzyme
Chemistry of Sulfonamides
Describe the mechanism of action of trimethoprim in the reaction of dihydrofolate reductase (DHFR) in the conversion of dihydrofolate to tetrahydrofolate and its relationship to other antifolates (ie. the anticancer drug methotrexate).
- TMP has 100,000x selectivity toward bacterial DHFR over human DHFR
- antifolate methotrexate is structurally more similar to folic acid and inhibits the human enzyme
Chemistry of Sulfonamides
Explain selectivity toward bacterial DHFR over human DHFR.
- TMP has 100,000x selectivity toward bacterial DHFR over human DHFR
Chemistry of Sulfonamides
What is sequential blocking?
complementation of two agents that act on different steps of the same metabolic pathway, resulting in synergistic behaviour
Chemistry of Sulfonamides
Describe an example of sequential blocking.
cotrimoxazole – combination of sulfamethoxazole (SMX) and trimethoprim (TMP)
DHPPP → DGA → DHF → THF →N5-methyl THF
- DHPPP to DHA: SMX inhibits dihydropteroate synthase
- DHF to THF: TMP inhibits dihydrofolate reductase
Chemistry of Sulfonamides
What are the advantages of sequential blocking?
- lower dosing of both compounds
- broader spectrum of activity
- less resistance (unless organism is resistant to one drug prior to therapy)
Chemistry of Superoxide Generators
Describe the structural features of nitrofurantoin and metronidazole (ie. the functional group responsible for superoxide generation).
they are both nitroheteroaromatic compounds
O––N==O
Chemistry of Superoxide Generators
Explain the mechanism of action of these drugs.
nitrofurantoin and metronidazole inhibit DNA and RNA functions through mechanisms that are complex and non-specific
- reduction of the nitro group creates reactive species that are capable of covalently attaching to and disrupting nucleic acid and protein functions
- selectivity is achieved by more efficient reduction of drugs in bacteria, particularly in anaerobes
Chemistry of Superoxide Generators
Describe how nitrofurantoin and metronidazole help to facilitate superoxide generation in bacteria.
–
Chemistry of Superoxide Generators
What are reactive oxygen species (ROS)?
cause damage
- superoxide
- hydrogen peroxide
- hydroxyl radical
