Aminoglycosides Flashcards
General Properties of Aminoglycosides
Main structure
Spectrum?
Toxic?
Solubility in water?
Protein binding?
which ones are cidal?
Metabolism?
MOA of Aminoglycosides?
- AGs interact at t-RNA binding site of 30s ribosomal particle causing mistranslation of m-RNA leading to NONsense proteins
- Has a low log p so it needs to be transported
- Incorporation of misfolded protein into cell membrane allows more antibiotic to enter
- Cessation of protein biosynthesis
- Membran leaks K+ leading to death
- Secondary mechanism is oxidative stress–>Cell death
Kanamycin the prototypical structure for amino glycosides, using the structure what do you know about it?
- Resistance happens quickly with AME enzymes because all of its functional groups are either hydroxyl or amine
- Structurally related to Tobramycin and Amikacin
- Used to be used in anti TB cocktails
- Extensive modification by R-factor enzymes at the C3 and C6 site inactivating it (repeat)
- Not used anymore
Resistance to Aminoglycosides
4 in total
- Enzymatic modification of AG (over 120 different AG-modifying enzymes are known)
- N-acetylation [AAC = aminoglycoside acetyl transferases]
- O-phosphorylation [APH = aminoglycoside phosphotransferases]
- O-adenylation [ANT = aminoglycoside adenyltransferases]
Resistance by enzymatic modification is structurally dependent. The altered drugs interact with bacterial ribosomes more weakly than the parent drugs.
- Poor uptake (can be intrinsic)
- Efflux
- Ribosomal mutations leading to decreased sensitivity (seems to involve automethylation of certain RNA bases)
AMEs Covalently Modify and Deactivate AGs
With an AME what happens?
What is the goal?
- With an AME-
- Inactivated drug –> Poor binding to ribosomes–> Increases the MIC–>Causes phenotypic resistance
- The goal it to overcome the action of the AMEs
- —> Then you retain high concentrations —>lowers MIC–> Overcome resistance
- Analogs are doing just this (Tobra, Genta, Amakacin)- These incorporate structures that overcome the action of the resistance so you can maintain a higher concentration so the concentration need is much lower this has a direct effect on resistance
AMEs dictate spectrum of coverage
Genes Encoding AMEs Found on Plasmids AND Chromosomes
Can spread in what ways through population?
Some bacteria are more prone to share?
And some are more prone to?
- AME-based resistance can be spread vertically or horizontally through a population
- Some bacteria are more prone to share genes vertically
- Some bacteria are more prone to share genes horizontally
Rationally Designed Analogs To Overcome Resistance
Tobramycin Sulfate
Used for what type of bacteria?
Gram negative
Gentamicin Sulfate
Lacks what ?
- Lacks the two functional OHs on the C3 and C6 making it have an even better spectrum for gram (+)
Amikacin?
What makes this so good?
- In many cases can over come bacteria that are resistant to Tobramycin or Gentamycin because it contains a HABA group
- So a bacteria can have a bunch of AMEs but it wont recognize the structure of the drug
Spectinomycin this one is different why?
- Has a different main structure and is static all other aminoglycosides are cidal
- Treats TB and STDs
Streptomycin
Used?
Used in cocktails but resistance is common
First drug to ever get a blind study in 1946
Systemic therapy with AGs
Combinations of what?
What type of approach?
- Systemic therapy often used in combination with B-lactams and Vancomycin
- Synergistic aproach
Gentamicin More Gram?
What does it cover?
- Positive
- Covers S. Aureus
- Viridans, Streptococcus
- Enterococcus spp
Clinical properties and uses
Class toxicities of AGs
Spectrum coverage for AGs
