Infectious Disease Flashcards Guo - Protein Synthesis Inhibitors

Front 1

What is the MOA of aminoglycosides?

Back 1

Binds to the 30s ribosomal subunit of prokaryotes --> preventing formation of the initiation complex and causes mRNA misreading

They generate defect bacterial proteins that impair the bacteria cytoplasmic membrane and enhance further drug penetration

Front 2

What is the MOA of tetracyclines?

Back 2

Binds to the 30s ribosomal subunit and inhibits binding of aminoacyl-tRNA to the A site

Front 3

What is the MOA of chloramphenicol?

Back 3

Binds to the 50s ribosomal subunit and inhibits peptidyltransferase

Front 4

What is the MOA of macrolides/ketolide?

Back 4

Binds to the 50s ribosomal subunit and prevents translocation

Front 5

What are the most clinically used aminoglycosides?

Back 5

gentamycin
tobramycin
amikacin

Front 6

what are the general chemical features of aminoglycosides?

Back 6

1,3-diaminoinositol moiety (links to other sugar residues to give oligosaccharide-type molecules)

(+) charged at pH 7.4

Highly polar w/numerous hydroxy groups

Highly water soluble

Front 7

Major toxicities with aminoglycosides (2)

Back 7

Renal Toxicity
Ototoxicity with delayed onset

Front 8

Method of entering cell for aminoglycosides

Back 8

Diffusion across porins followed by uptake by a transporter system that is dependent on energy and the cytoplasmic membrane electric potential

Front 9

Mechanisms of Resistance of Aminoglycosides

Back 9

1. Enzymatic inactivation - MOST COMMON IN CLINIC (N-acetyltransferases, O-phosphotransferases, O-nucleotidyltransferases)

2. Decreased Transport - mutations of or less of the active uptake transporters (cross-resistance usually occurs among different aminoglycosides)

3. Point mutations in 30s ribosomal subunit proteins - decreased binding of the aminoglycosides (more than one binding site is involved so resistance to one may not cross to the action of others)

Front 10

Which two aminoglycosides are the most resistant to the inducible metabolic enzymes and if resistance to these two drugs have developed, then cross resistance to all other aminoglycosides will occur?

Back 10

Amikacin
Netilmicin

Front 11

What are 3 bacterial enzymes (from lecture) that can inactivate aminoglycosides?

Back 11

AAC - aminoglycoside actetylase
ANT - aminoglycoside nucleotide transferase
APH - aminoglycoside phosphorylase

Front 12

What structural features in Amikacin hinder enzymatic inactivation?

Back 12

A long-amine-substitution at N1 of diaminoinositol ring hinders the modifications at both neighboring and remote amino/hydroxy groups

Front 13

What structural features in Netilmicin hinder enzymatic inactivation?

Back 13

1. Ethyl substitution at N1 of diaminoinositol prevents the acetylation on the group

2. Less hydroxy groups on sugar residues attached to the diaminoinositol ring

3. Methyl groups at 4'-C hinders modification of 4'-OH

Front 14

How do tetracyclines enter bacterial cells?

Back 14

Active transport across cell membrane (inner membrane for gram negative)

Front 15

What ion complexes with tetracyclines that allows them to bind to a specific site on the aminoacyl-tRNA binding site on the 30s ribosome unit, inhibiting protein synthesis

Back 15

Mg2+

Front 16

True or false: tetracyclines are bacteriocidal

Back 16

false, bacteriostatic - tetracyclines do not allow the synthesis of non-functional or partially functional proteins

Front 17

True or false: tetracyclines are just as potent as aminoglycosides

Back 17

False, they do not bind to the ribosomes as tightly as aminoglycosides and so are less potent

Front 18

Where do tetracycline/Ca2+ complexes deposit and in what patient population should not take this drug due to this effect?

Back 18

bones and teeth

so not recommended for kids who are still developing teeth

Front 19

What structure in demeclocycline attached to the unsaturated ring system increases its photosensitivity risk and generation of free radicals?

Back 19

Chlorine

Front 20

which two tetracyclines are the most potent and stable (hint: both are taken BID)

Back 20

Minocycline
Doxycycline

Front 21

True or false: tetracyclines have the broadest spectrum of activity but are less potent

Back 21

True

(penicillins are preferred for serious G+ bacteria and aminoglycosides/cephalosporins are preferred for serious G- infections)

Front 22

Which new glycine-derived tetracycline is more potent in vitro and has been developed for treating infections caused by bacteria strains that are resistant to commonly used tetracyclines, methicillin or vancomycin?

Back 22

Tigecyclin

Front 23

What are the mechanisms of resistance for tetracyclines?

Back 23

1. Loss of accumulation - mutations of the uptake pumps and induction of efflux pumps, cross-resistance is common

2. Induction by bacterial cells of ribosome protection proteins - they bind to the 30s subunits in a way that blocks only the tetracyclines and not the aminoacyl-tRNA, CROSS RESISTANCE TO ALL TETRACYCLINES OCCUR

3. Enzymatic oxidative metabolism inactivation - rare and of minor clinical significance

Front 24

What are the structural features of macrolides (other than the fact that they have big molecular weight)?

Back 24

1. A large lactone ring, hence name "macrolide"

2. A ketone group at C9 except in azithromycin

3. A glycosidically linked sugar residue at C3

4. A glycosidically linked aminosugar (also in aminoglycosides) at C5

Front 25

What are the 3 macrolide drugs commonly marketed in the U.S.?

Back 25

Azithromycin
Clarithromycin
Erythromycin

Front 26

How do macrolides enter bacteria?

Back 26

Passive diffusion

Front 27

True or false: Macrolides penetrate bacteria better at a low pH

Back 27

False, since they contain a (+) charged tert-nitrogen, they penetrate better at a high pH (alkaline tissue)

Front 28

True or False: Gram (+) bacteria accumulate up to 100x more erythromycin than gram (-) organisms

Back 28

True

Front 29

True or false: Macrolides are more active on anaerobic gram (+) organisms

Back 29

False, more active on aerobic gram (+) organisms

Front 30

Are macrolides bacteriocidal or static?

Back 30

Bacteriostatic

Front 31

Binding of erythromycin to the 50s ribosome inhibits binding of what other 50s ribosome-binding antibiotics?

Back 31

Chloramphenicol
Streptogramins
Clindamycin

Front 32

Spiroketal formation catalyzed by acid causes what side effect of macrolides?

Back 32

GI cramping

Front 33

Which macrolide has its 6-OH group blocked by a methyl group which prevents spiroketal formation? What happens as a result of this block?

Back 33

Clarithromycin

Spiroketal formation block reduces GI cramping and it makes the drug more stable, leading to higher plasma levels

Front 34

Macolides inhibit what process of protein synthesis?

Back 34

translocation, via inhibition of the growing chain from the A site to the P site of the 50s subunit

Front 35

How does azithromycin prevent spiroketal formation?

Back 35

A basic N-methyl group has been inserted between C9 and C10 and the carbonyl moiety is eliminated

Front 36

What other characteristics does azithromycin have?

Back 36

longer plasma half-life from greater and longer tissue penetration

significant post-antibiotic effect

QD dosing

More active against gram (-) bacteria than erythromycin and clarithromycin

Front 37

What are the mechanisms of resistance for macrolides?

Back 37

1. Decreased binding - plasma-mediated introduction of an RNA methylase (an adenine group in one of the rRNA strands of the 50s is methylated - methylation dec. binding of erythromycin)

2. Cross resistance to other macrolides, lincosamides (lincomycin and clindamycin) and streptogramin B (quinupristin) - MSLB RESISTANCE, THE MOST IMPORTANT MECH OF RESISTANCE

3. Induction of efflux pumps

4. Induction of an esterase enzyme (lactonase) that hydrolyzes the lactone ring --> inactivates the macrolide

Front 38

What is Telithromycin? What are it's characterisitics?

Back 38

A ketolide

A semisynthetic derivative of erythromycin

3-Keto group is in place of a sugar residue

It has a substituted carbamate at C11-C12

Less susceptible to MLSB and efflux-mediated (mef or msr) mechanisms of resistance

Similar spectrum of activity to macrolides but more active against a number of macrolide-resistant gram(+) strains

Front 39

Name two lincosamides

Back 39

Lincomycin
Clindamycin

Front 40

Clindamycin is good against what type of bacteria

Back 40

Gram (+), good for those hypersensative to beta-lactams

Front 41

What is the major complaint for Clindamycin?

Back 41

GI upset (e.g. pseudomembranous colitis by Clostridium difficile)

Front 42

Which bacteria is clindamycin good for when applied topically to comedones?

Back 42

Propionobacterium acnes

Front 43

What is the MOA of lincosaminides?

Back 43

similar to that of erythromycin - binds to the same 50s ribosomal subunits and inhibits protein synthesis in the same manner

Front 44

What is the mechanism of resistance to clindamycin?

Back 44

Cross resistance to the rRNA methylase alteration does occur with clindamycin (MLSB resistance)

Front 45

What are the two types of Ribosomal Binding Sites of Protein Inhibitor Antibiotics and its representative drugs?

Back 45

Streptogramin A - dalfopristin

Streptogramin B - quinupristin

Front 46

How is streptogramin A structurally different from streptogramin B?

Back 46

Streptogramin A has a large polyunsaturated, non-peptide ring

Streptogramin B are cyclic peptides

Front 47

How is streptogramin A different from streptogramin B by the way they inhibit bacterial protein synthesis?

Back 47

Type A distorts the ribosome to prevent binding of the t-RNA

Type B are thought to block translocation of the growing peptide

(together they facilitate each other's binding since they attach to different sites - synergistic)

Front 48

Against what organism is dalfopristin and quinupristin is used in combination?

Back 48

MRSA