Lecture 7 - Med Chem Antibiotics 2 Flashcards
Agents with an action site on 30S ribosomal subunit
Aminoglycosides
Tetracyclines
Agents with an action site on the 50S ribosomal subunit
Erythromycin + other semi-synthetic macrolides Lincosamides Chloramphenicol Streptogramins Oxazolidinones
3 pharmacophoric 1,3-diaminoinositol moiety found in Aminoglycosides are…
Streptamine
2-deoxystreptamine
Spectinamine
Aminoglycoside info
freely soluble at all achievable pHs
are basic and form acid addition salts
not absorbed in significant amounts in GI track
excreted in active form in high conc
** V polar, accumulates in nephrons = nephrotoxicity + kidney failure***
When given orally, action is primarily confined to where for Aminoglycosides?
GI track
Aminoglycoside spectra
broad spectra but toxicity limits clinical use to severe infections by gram -
Aminoglycoside toxicities
Ototoxicity to functions mediated by 8th cranial nerve
ex. hearing loss, vertigo
can also lead to kidney tubular necrosis
Levels of protein binding ahminoglycosides?
Low lvls, widely distributed in extracellular fluids
Mechanism of action Aminoglycosides
- Bactericidal due to combo of toxicity
- charge, enter bacterial cell walls…bind to - charge LPS and diffuse into walls in small amount
- uptake process inhibited by Ca and Mg ions, so dont take supplement w/ antibiotics
- drug will destroy semipermeability of cell membrane and more come in and cause death
- at increased conc, protein biosynthesis ceases
What portion of 30S do aminoglycosides bind?
Bind to 16S ribosomal RNA portion
impairing proof reading function
Bacterial Resistance Aminoglycosides
- compound modified outside the cell, poor uptake = resistance
- enzymes can acetylate the amino groups and phosphorylate/adenylate the hydroxyl groups which are essential to binding ribosomal proteins
- Anaerobic organisms such as Bacteroides are resistant, lac oxygen dependent transport to move drug across membrane
N-acylation aminoglycoside due to….
AAC-aminoglycoside acetylate
O-phosphorylation amino glycoside due to….
APH-aminoglycoside phosphorylase
O-adenylation amino glycoside due to….
ANT-aminoglycoside nucleotide transferase
Kanamycin
mixture of 3 components
2nd line for M.tuberculosis
only utilized to treat resistant organisms and used in combo with others
Parenteral form only
What is Kanamaycin unstable to?
R-factor enzymes
O-phosphorylated at C3, N-acetylated at C6
transformation products inactive antibiotically
Amikacin
made semi synthetically from kanamycin A
HABA moiety at N3 inhibits adenylation and phosphorylation in the distant amino sugar ring (C3/C2)…this is due to decreased binding to R-factor mediated enzymes
This change, strong enhanced potency and spectrum
Tobramycin
Lack C3 hydroxyl group = not substrate for APH(3)-1 = broader spectrum than kanamycin
Substrate at C2 by ANT, acetylation at C3 by AAC and C2 by AAC
widely used parenterally for difficult infections
Gentamicin
Spectrum is enhanced as some of the functional groups serve as targets for R-factor
less $$
inactivated via C2 adenylation + acetylation at C6/C2
used in UTI, burns, some pneumonias, bone + joint infections by gram -
Aminoglycoside incompatibility issue
When combo w/ certain B-lactam, the two drugs react w/ each other so that N-acylation of C-1 of C1 of gentamicin by B-lactam takes plus..inactivaitng both
2 agents shouldn’t be mixed in same solution and admin in different tissue compartments (ie 1 in each arm)
Streptomycin (STM)
water soluble w/ basic properties
results in v poor absorption from GI tract and commonly given IM
Streptomycin MOA
inhibits protein synthesis, but addition effects on misreading of a mRNA template and membrane damage may contribute to bactericidal action of STM
Streptomycin Metabolsim
- metabolism impacted as major mech of resistance
- adenyltransferase catalyzes adenylation of C3 hydroxyl group to give O-3-adenylate and phosphotransferase turns same C-3 into 0-3-phosphorylate
results in metabolite that won’t bind to RNA
Tetracycline MOA
inhibits protein synthesis at ribosomal lvl leading to bacteriostasis
Tetracyclines info
- Chelation: incompatibility w/ cadmic multivalent ion rich antacids and consumption of dairy products
- IM = painful, cadmic with EDTA + buffered at acidic pH where chelation is less pronounced and watersolubility is higher.
- old samples lose half of their potency due to epimerization
Semi-synthetic tetracyclines
- Doxy- + minocycline = longer T1/2
- both good oral bioavailability and given once a day
- Absorption lowered by 20% coadmin w/ milk+food
- Mino vestibular toxicities not shared with other tetracyclines
Macrolide info
- safest abx in common se, URT + LRT + soft tissue
- derived from large lactone ring
- contains 2 or more characteristic sugars ( cladinose + desosamine)
- weakly basic amino group in sugars
- salt form = improve water solubility
2 characteristic sugars of Macrolide?
Cladinose and Desosamine
Chemical properties of Macrolides
- chemical instability of earlier ones due to acid-catalyzed internal metal formation resulting in bio-inactivation
Minimized by admin in coated tabs
Macrolides MOA
Bind to 23S rRNA in polypeptide exit tunnel adjacent to peptides transfer center in 50S ribosomal unit
Peptide formation/elongation step is inhibited
Extensive cross resistance between macrolides because….
they bind in the same vicinity in 50S ribosomal subunit
What mediates bacterial resistance through R-factor enzymes for macrolides?
Methylation of specific guanidine residues on their specific ribosomal RNAs to inhibit/reduce macrolide binding
Clarithromycin info
C6 hydroxyl group converted to C6 methoxy to prevent internal attack on keto group to form metal
Methoxy group offers more lipophilicity to compound + prevents metal formation
This gives better blood lvls but also less gi upset
Azithromycin
conversion in erythromycin or clarithromycin ….N-methyl group inserted between C9/C10 and carbonyl moiety is absent
doesn’t form metal intermediate, more aid stable, considerable long life
Lincosamide MOA
bind to 50S ribosomal sub particle at site partly overlapping w/ macrolide binding site and are mutually cross-resistant with macrolides
similar MOA to macrolides
Chemical properties Lincosamides
Weakly basic, salt form w/ acid improve solubility
Metabolism Lincosamides
extensive liver metabolism resulting primarily in N-demethylation
N-desmethyl analog retains biological activity
Lincomycin + Clindamycin are….
structurally related
SN2 run on Lincomycin replaces OH group w/ CL group with inversion of configuration R C7 to S C7
Clinda more potent + lipophilic & better absorbed following oral admin
Chloramphenicol info
neutral compound poor/mod solubility. improved by forming prodrug
2 chiral centers, 4 stereoisomers possible
givenly orally, rapidly absorbed + short 1/2 life
Which stereoisomers of Chloramphenicol are significantly active?
1R, 2R
Chloramphenicol MOA
binds 50S sub particle region.
resistance developed through acetylation of free OH groups by R-factor mediated enzymes.
acetylated production no longer binds ribosomes and is inactive
Streptogramins
VRSA and VRE usage
synergy observed when using A + B
Quinuprisint + Dalfoprisitn
Synercid, 30:70 ratio
combo streptogrmains for IV
Dalfoprisitin binds 70S particle of A/P sites
Quinupristin binds A/P site too
drugs are bacteriostatic when admin solo, bactericidal when admin together
Dalfoprisitn creates high affinity binding site for quinupristin
Linezolid info
- effective against gram +
- Gram - intrinsically resistant due to endogenous efflux pumps
- well absorbed orally, comes as tab, iv, suspenison
Linezolid MOA
binds to 50S sub particle preventing the formation of functional initiation complex
Linezolid metabolism
significant oxidative metabolism occurs by oxidation of morpholine ring. Metabolites don’t retain antibacterial activity
