03 Study Guide: Protein Synthesis inhibiting antibiotics

Question 1

What is the major class of bactericidal protein synthesis-inhibiting antibiotics, and how can one recognize names of drugs in each class?

Answer 1

Aminoglycosides (-mycin/-micin): gentamicin, tobramycin, amikacin

Question 2

Name 6 classes (and 1 additional drug) that are examples of bacteriostatic protein synthesis inhibiting antibiotics.

Answer 2

Tetracyclines (-cycline)
Macroclides (-thromycin/-xomycin)
Lincosamides (-lin-)
Streptogramins (-prisitin) 
Oxazolodonones (-zolid)
Chloramphenicol

The Man Loves Strep Of Course

Question 3

For each of the classes of bacteriostatic protein synthesis inhibitors (except glycylcyclines, which have only one member), list the portion of the name that is similar among the drugs in each class.

Answer 3

Tetracyclines (-cycline) : Doxycycline, Minocycline

Macroclides (-thromycin/-xomycin): Erythromycin, Clarithromycin, Azithromycin, Fidaxomycin

Lincosamides (-lin-): Clindamycin

Streptogramins (-prisitin): Dalfoprisitn/ Quinupristin

Oxazolodonones (-zolid): Linezolid, Tedizolid

Chloramphenicol

Question 4

Name one aminoglycoside antibiotic that does not follow the aminoglycoside naming convention.

Answer 4

Amikacin

Question 5

What are the two major subunits of the bacterial ribosome?

Answer 5

Large ribsomoal subunit and small ribosomal subunit

Question 6

What are the 3 major steps in protein synthesis – what happens in each step?

Answer 6

Initiation: tRNA brings first amino acid in polypeptide chain to bind to start codon on mRNA

Elongation: tRNAs bring amino acids one by one to add to polypeptide

Termination: release factor recognizes stop codon, translational complex dissociates and completed polypeptide is released

Question 7

Interferes with Initiation complex function (1 class):

Answer 7

Aminoglycosides (16S and 30S)

Question 8

impairs Proofreading (1 class):

Answer 8

Aminoglycosides

Question 9

interferes/ inhibits tRNA binding at the A site and / or peptide bond formation (6 classes

Answer 9

• Tetracyclines (16S on 30S)
• Glycylclines
• Lincosamides (23S on 50S)
• Streptogramins (23S on 50S)
• Oxazolidinones (23S on 50S)
• Chloramphenicol (23S on 50S)

Question 10

block Exit of the polypeptide from the ribosome (2 classes)

Answer 10

Macrolides (23S on 50S)

Streptogramins

Question 11

For the bactericidal class of protein synthesis-inhibiting antibiotics, what 3 types of processes are thought to contribute to the bactericidal effect?

Answer 11

• Formation of free radicals, which damage the cell
• Formation of holes in the cell membrane
• Formation of toxic aggregates inside the cell

Question 12

What 2 steps are required for aminoglycoside antibiotics to reach their target site in gram negative bacteria?

Answer 12

1) Passive diffusion across outer membrane
- Normal entry through porins OR can disrupt lipopolysaccharides (LPS) function to enable movement across outer membrane

2) Active transport across cell membrane into cytoplasm (O2 dependent)
- Anaerobes cannot bring aminoglycosides, requires energy gradient created by proton pump
- Low extracelleular pH and lack of O2 dissipate that gradient

Question 13

How do each of the following impact cellular uptake of aminoglycosides in gram negative bacteria?

Answer 13

• LPS : disrupting LPS allows for movement across outer membrane
• Porins : polar drugs cannot cross membrane except through porins
• Oxygen : lack of oxygen dissipates gradient
• pH: low extracellular pH dissipates gradient

Question 14

Are anaerobic bacteria susceptible to aminoglycoside antibiotics? Why or why not?

Answer 14

Anaerobic bacteria cannot bring aminoglycosides in because oxygen is required to drive the transport process, therefore they are not susceptible.
- Active transport across cell membrane is O2 dependent

Question 15

What is the basis for gram positive bacteria’s intrinsic resistance to aminoglycosides?

Answer 15

1)Alteration or deletion of the target receptor protein on the 30S

2) Impaired drug uptake by:
- Mutation or deletion of a porin
- Mutation of struction involved in electrochemical gradient maintenance
- Growth conditions where O2 dependent transport process is not functional

3)Production of transferase enzymes that inactivate the aminoglycoside

Question 16

Compare the process of cellular uptake between aminoglycoside and tetracycline antibiotics.

Answer 16

Aminoglycosides: combined with B lactam to create holes in peptidoglycan cell wall, allowing aminoglycoside to enter

Tetracycline: complexes with metal cations and attracts them to specific porins → accumulation in periplasm
-Uptake into cytopalsm is energy-dependent, driven by the pH gradient difference

Question 17

Describe how bacteria alter (or protect) their antibiotic binding targets against aminoglycosides vs. tetracyclines

Answer 17

Aminoglycoside: antibiotics target the small 30S subunit and bind at the 16S rRNA site causing:

• Interference with the initiation complex
• Production of faulty miscoded proteins, by interfering with proofreading

Tetracycline: bind reversibly to 16S site on small 30S subunit
Drug blocks the site

Question 18

What is the function of a ribosomal protection protein?

Answer 18

Ribosomal protection proteins prevent tetracyclines from binding to the ribosome, allowing translation and protein synthesis to continue
Part of tetracycline resistance

Question 19

Compare the resistance mechanisms by which bacteria limit concentrations of aminoglycosides vs. tetracyclines.

Answer 19

Aminoglycosides: inactivation from chemical modification by transferase enzymes
-Generally transferred horizontally between bacteria by plasmids

Tetracyclines: bind to repressor protein (Tet(R)) resulting in dissociation from mRNA and facilitates teh expression of tetracyline specific efflux pump

Question 20

What is a TetR protein and what is its role in antibiotic resistance?

Answer 20

TetR prevents accumulation by increasing efflux which confers resistance to all tetracyclines

Question 21

How do bacteria alter aminoglycosides to develop resistance to them (what’s the category of enzyme that is responsible)?

Answer 21

Transferase enzymes will chemically modify the aminoglycosides to develop resistance

Question 22

Are glycylcyclines affected by the resistance mechanisms that affect other protein synthesis-inhibiting antibiotics?

Answer 22

Glycylcyclines are designed to avoid tetracycline resistance; not affected by ribosomal protection pumps (RPPs) or efflux pumps

Question 23

Do aminoglycosides have activity against anaerobes? Why or why not?

Answer 23

Aminoglycosides do not have activity against anaerobes because there is no oxygen to drive the process

Question 24

Which class of protein synthesis inhibiting antibiotics has particularly good activity against atypical pathogens like rickettsieae and Vibrio?

Answer 24

Tetracyclines

Question 25

In addition to clindamycin (linocosamides) and gentamicin (aminoglycosides), what 3 classes of protein synthesis inhibiting antibiotics have particularly good activity against drug-resistant pathogens?

Answer 25

Streptogramins (-pristin): Dalforpristin / quinupristin

Oxazolidinones (-zolid): Linezolid / Tedizolid

Macrolides (-thromcin / -xomycin): Erythromycin /Clarithromycin / Azithromycin / Fidaxomycin

Question 26

Which class is often used as eyedrops for eye infections?

Answer 26

Aminoglycosides: tobramycin and gentamicin

Question 27

Which class is useful for COPD / asthma exacerbations?

Answer 27

Macrolides: due to anti-inflammatory and immunomodulating characteristics; erythromycin, clarithromycin, azithromycin, fidaxomycin

Question 28

Which DRUG is used in inhaled form for treating bacterial infections in cystic fibrosis?

Answer 28

Tobramycin: treat P. aeruginosa in cystic fibrosis

Monobactam, aztreonam is used similarly

Question 29

Which drug class, due to dependence on renal clearance, is dosed based on body weight and creatinine clearance and requires concentration monitoring?

Answer 29

Aminoglycosides

Question 30

Which class has basically no oral absorption?

Answer 30

Aminoglycosides→ entire oral dose goes to feces; usually given IM or IV

Question 31

Which 2 classes are only available by IV route?

Answer 31

Streptogramins (dalfopristin/quinupristin) and Glycylcyclines (tigecycline)

Question 32

Which class cannot be taken with dairy products or antacids, and why?

Answer 32

Tetracyclines; dairy products impair absorption

- Multivalent cations and alkaline pH also impair absorption

Question 33

Which class must be enteric coated to avoid destruction by stomach acid?

Answer 33

Macrolides

Question 34

Which class is associated with nephrotoxicity and ototoxicity?

Answer 34

Aminoglycosides

Question 35

Which class is associated with GI effects (and why?), hepatic toxicity, QT interval prolongation, and hearing loss?

Answer 35

Macrolides: GI effects (due to stimulation of gut motility via motion receptors), heart rhythm, hepatic toxicity, and drug interactions (P450 inhibitors)

Question 36

Which class is associated with phototoxicity, bone / tooth toxicity, and hepatic toxicity?

Answer 36

Tetracyclines

Question 37

Which class should not be administered to children or pregnant women, and why?

Answer 37

Tetracyclines

Question 38

What are 5 advantages of docycyline vs. most other tetracyclines?

Answer 38

• Available PO and IV
• Can be administered with food
• Less likely to produce photosensitivity
• Less calcium binding ( only tetracycline that can be given to kids under 8 yers old)
• Clearance is non-renal

Question 39

What two protein synthesis-inhibiting antibiotic agents have been associated with increased mortality risk?

Answer 39

Glycylcyclines (Tigecycline)

Question 40

Which drug presents a risk for development of serotonin syndrome?

Answer 40

Linezolid (PO/IV); caution with antidepressants

Question 41

Which drug is rarely used now, due to risk of bone marrow suppression, fatal aplastic anemia and gray baby syndrome?

Answer 41

Chloramphenicol; broad spectrum

Question 42

Which protein synthesis-inhibiting antibiotic class is given with aminoglycosides, and why?

Answer 42

Combined with B lactams when needing to treat gram positive bacteria to create holes in peptidoglycan cell wall, allowing aminoglycosides to enter

Question 43

Which protein synthesis-inhibiting agent is available as a 2-drug combination, and what is the advantage of combining the two?

Answer 43

Streptogramins: Dalfopristin / Quinupristin→ synergistic effects = rapidly bactericidal