Antibiotics II Flashcards
(25 cards)
List the drugs that target the ribosomes
- Aminoglycosides (30S)
- Chloramphenicol (50S)
- Glycylcylines (30S)
- Macrolides (50S)
- Oxazolidinones (50S)
- Streptogramins (50S)
- Tetracyclines (30S)
Aminoglycosides history
-isolated from streptomyces griseus in 1944
-at physiological pH, they are positively charged and cationic
-primary targets are negatively charged Gram-negative LPS and ribosomal RNA
- bind to the 30s subunit of the ribosome
-produces conformation change that impacts translational fidelity and causes the accumulation of truncated and nonfunctional proteins
-bactericidal
-very effective against most aerobic/facultative gram-negative bacilli (not Stenotrophomons or Burkholderia)
-not great for gram positives, can work against MSSA
-can behave synergistically with cell wall agents such as beta-lactams (enhanced uptake of in Enterococci)
** Test with high-level concentration against enterococci
IV use only
What do aminoglycosides target?
-block the initiation of translation and cause the misreading of mRNA
Aminoglycosides antibiotics
-are a complex family of compounds characterized for having an aminocyclitol nucleus *steptamine, 2-deoxystreptamine, or streptidine) linked to amino sugar through glycosidic bonds
Name the aminoglycosides
- streptomycin
- neomycin
- kanamycin
- paromomycin
- spectinomycin
- gentamicin
- tobramycin
- sisomicin
- dibekacin
10, amikacin - netilmicin
- isepamicin
Three main mechanisms of resistance: Aminoglycosides
- decreased permeability, efflux pumps (ex: PA)
- Methylation of 16s rRNA enzymes (ArmA and RmtA)
- Mobilization aminoglycoside modifying enzymes (AMEs)
* N-acetylation (ACE)
* O-adenylation (ANT)
* O-phosphorylation (APH)
Macrolides history
-erythromycin was discovered as a product of the soil bacterium streptomyces erythreus in the Philippines in the 1950s
- A mixture of different isomers, it has poor absorption and is easily activated by gastric acid
-Azithromycin and clarithromycin are synthetic forms designed to overcome those issues
-in most situations are bacteriostatic
-due to poor penetration of the gram-negative outer membrane, use is limited to select gram negatives (Bordatella, Neisseria, Haemophilus)
-clarithromycin is somewhat better for Gram pos
-Azithromycin is somewhat better for Gram neg (especially H.Influenza, and M catarrhalis), poor for anaerobes
-clarithro has an important role in the treatment of M.avium and Helicobacter infections
-longstanding option for atypical pneumonia (ex: mycoplasma, chlamydia)
Macrolides: mechanism of action
-mechanisms of action involve the binding to 50S (23s rRNA) near the peptidlytransferase center and blocking the polypeptide exit channel
Macrolides antibiotics
-are a natural product consisting of a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine is attached
-macrolides polyketide class of natural products
-macrolides antibiotics are classified based on the number of atoms in the lactone ring
What groups are macrolide antibiotics classified into
- 14-membered antibiotics
- 15-membered antibiotics
- 16-membered antibiotics
Macrolides: resistance
-decreased uptake
-efflux
-mutations in the 23s rRna receptor site
-MLS phenotype
-the most common mechanism is mediated by erm genes
-dimethylation of adenine in 23s rRNA which produced a conformational change and drugs can no longer bind
-dimethylation of 23s rRNA blocks binding sites for macrolides, lincosamides, and streptogramins (MLS)
-can be constitutive or inducible by small quantities of macrolides (not lincosamides) = D test
-present in S. aureus, S. pyogenes, S.pneumoniae
Lincosamides
-isolated in 1962 from streptomyces lincolnensis in the soil of lincoln, Nebraska
-similar properties and spectrum to the macrolides, but structurally unrelated
-better at anaerobes than the macrolides (particularly B fragilis) though resistance is increasing
-resistance is primarily through the MLS
-clindamycin
Streptogramins
-exists as natural mixes of streptogramin A and streptogramin B (both are cyclic peptides)
-different forms isolated from different species of streptomyces
-most common is Synercid (Quinupristin-dalfopristin)
-Binds 50S portion of ribosomes (A and B bind different regions)
-active against most Gram positives (not E.faecalis) and some Gram-negatives
-not commonly used
-resistance is usually due MLS phenotype (ribosomal methylation blocking binding site)
Oxazolidinones
-linezolid
-produced completely by organic synthesis
-inhibit protein synthesis (mostly bacteriostatic)
-bind to 50S rRNA, prevent association with 30rRNA
-spectrum of activity is mostly against gram-positive (including MRSA and VRE)
-resistance is rare, with occasional mutations in 23s rRNA binding site
Tetracyclines
-discovered in 1948 by Duggar a botanist who collected ultra mold samples from all over the world and checked their anti-microbial properties
-discovered in Missouri soil, produced by streptomyces aureofaciens
-4 benzene ring core structure
- binds to 30s rRNA and inhibits aminoacyl-tRNA binding to ribosomal acceptor site- no chain elongation
-reversible (bacteriostatic)
-Very wide spectrum of activity: Gram pos, neg, intracellular, and some protozoans
-treatment choice for chlamydia, rickettsia, and spirochetes
Tetracycline resistance
-despite their wide spectrum, bacteriostatic nature and increasing resistance has limited their use a first-line agents with the exception of Borrelia, Rickettsia, Brucellosis, and others
-resistance was reported as early as 1953 in the Enterobacteriaceae
What are the two main mechanisms for Tetracycline resistance?
- efflux pump (MFS superfamily) not doxy and mino
- Ribosomal protection proteins (RPPs), commonly Tet(O) and Tet(M). These cytoplasmic proteins weaken the interaction of the drug with the ribosomes, ineffective against tigecycline
-resistance is uncommon among obligate intracellular (ex: Chlamydia and Rickettsia)
What is tigecycline?
-is a glycylcycline and is impervious to most mechanisms of tetracycline resistance
Chloramphenicol
-developed from soil organisms, streptomyces venezuelae
-binds to 50S
-bacteriostatic
-broad spectrum
-resistance is most often mediated by chloramphenicol acetyltransferase (Cat) genes that modify the drug
-not widely used in the US due to toxicity: Grey baby syndrome and bone marrow suppression
Fluoroquinolones
-core is a bicyclic ring structure with an N at position 1, a carbonyl at position 4, and a carboxyl group at position 3
-bactericidal
-The most common resistance mechanism is a stepwise mutation in the target active site
-plasmid-borne resistance mechanisms are also described as gnr genes that produce a protein that protects the target
-one of the AMEs, Aac(6’)-lb-cr, can also modify quinolones, causing resistance
ex: ciprofloxacin, levofloxacin, monofloxacin
What two targets do Fluoroquinolones inhibit?
- DNA gyrase: introduces negative superhelical twists. The primary target in gram negatives
- Topoisomerase IV: decatenates linked DNA molecules to allow for segregation into daughter cells. The primary target is gram positives
nitrofurantoin
-a compound with multiple bactericidal effects including inhibition of ribosomal translation and DNA damage
-restricted to UTIs, particularly gram neg (concentrates in urine)
-resistance is rare
-oral dosing
rifamycins
-bind and inhibit RNA polymerase
-resistance occurs fairly easily as point mutations in RNAP
-the spectrum is broad, Gram pos, neg, intracellular, mycobacteria
Sulfonamides
-structural analogs of PABA (ρ-aminobenzoic acid)
-block growth by interfering with folic acid synthesis
-cause decrease in bacterial nucleotide synthesis and inhibition of growth
-bacteriostatic
-broad spectrum (including some parasites)
-resistance often mediated by sul1- dihydropteroate synthase
-altered targets to avoid drug inhibition
-genes are plasmid-mediated and have spread widely among gram-negative
