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Microbiology lecture > Antibiotics II > Flashcards

Antibiotics II Flashcards

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1
Q

List the drugs that target the ribosomes

A
  1. Aminoglycosides (30S)
  2. Chloramphenicol (50S)
  3. Glycylcylines (30S)
  4. Macrolides (50S)
  5. Oxazolidinones (50S)
  6. Streptogramins (50S)
  7. Tetracyclines (30S)
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2
Q

Aminoglycosides history

A

-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

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3
Q

What do aminoglycosides target?

A

-block the initiation of translation and cause the misreading of mRNA

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4
Q

Aminoglycosides antibiotics

A

-are a complex family of compounds characterized for having an aminocyclitol nucleus *steptamine, 2-deoxystreptamine, or streptidine) linked to amino sugar through glycosidic bonds

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5
Q

Name the aminoglycosides

A
  1. streptomycin
  2. neomycin
  3. kanamycin
  4. paromomycin
  5. spectinomycin
  6. gentamicin
  7. tobramycin
  8. sisomicin
  9. dibekacin
    10, amikacin
  10. netilmicin
  11. isepamicin
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6
Q

Three main mechanisms of resistance: Aminoglycosides

A
  1. decreased permeability, efflux pumps (ex: PA)
  2. Methylation of 16s rRNA enzymes (ArmA and RmtA)
  3. Mobilization aminoglycoside modifying enzymes (AMEs)
    * N-acetylation (ACE)
    * O-adenylation (ANT)
    * O-phosphorylation (APH)
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7
Q

Macrolides history

A

-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)

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8
Q

Macrolides: mechanism of action

A

-mechanisms of action involve the binding to 50S (23s rRNA) near the peptidlytransferase center and blocking the polypeptide exit channel

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9
Q

Macrolides antibiotics

A

-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

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10
Q

What groups are macrolide antibiotics classified into

A
  1. 14-membered antibiotics
  2. 15-membered antibiotics
  3. 16-membered antibiotics
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11
Q

Macrolides: resistance

A

-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

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12
Q

Lincosamides

A

-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

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13
Q

Streptogramins

A

-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)

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14
Q

Oxazolidinones

A

-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

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15
Q

Tetracyclines

A

-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

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16
Q

Tetracycline resistance

A

-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

17
Q

What are the two main mechanisms for Tetracycline resistance?

A
  1. efflux pump (MFS superfamily) not doxy and mino
  2. 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)
18
Q

What is tigecycline?

A

-is a glycylcycline and is impervious to most mechanisms of tetracycline resistance

19
Q

Chloramphenicol

A

-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

20
Q

Fluoroquinolones

A

-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

21
Q

What two targets do Fluoroquinolones inhibit?

A
  1. DNA gyrase: introduces negative superhelical twists. The primary target in gram negatives
  2. Topoisomerase IV: decatenates linked DNA molecules to allow for segregation into daughter cells. The primary target is gram positives
22
Q

nitrofurantoin

A

-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

23
Q

rifamycins

A

-bind and inhibit RNA polymerase
-resistance occurs fairly easily as point mutations in RNAP
-the spectrum is broad, Gram pos, neg, intracellular, mycobacteria

24
Q

Sulfonamides

A

-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

25
Q

Trimethoprim

A

-structural analog of pteridine portion of dihydrofolic acid
-inhibits bacterial dihydrofolate reductase (works after sulfonamides)
-bacteriostatic
-broad spectrum
-often together in a combination drug, trimethoprim-sulfamethoxazole (Bactrim)
-resistance mediated by DHFR dihydrofolate reductase
-altered targets to avoid drug inhibition
-genes are plasmid-mediated and have spread widely among gram-negative

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