03 Study Guide: Protein Synthesis inhibiting antibiotics Flashcards
What is the major class of bactericidal protein synthesis-inhibiting antibiotics, and how can one recognize names of drugs in each class?
Aminoglycosides (-mycin/-micin): gentamicin, tobramycin, amikacin
Name 6 classes (and 1 additional drug) that are examples of bacteriostatic protein synthesis inhibiting antibiotics.
Tetracyclines (-cycline) Macroclides (-thromycin/-xomycin) Lincosamides (-lin-) Streptogramins (-prisitin) Oxazolodonones (-zolid) Chloramphenicol
The Man Loves Strep Of Course
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.
Tetracyclines (-cycline) : Doxycycline, Minocycline
Macroclides (-thromycin/-xomycin): Erythromycin, Clarithromycin, Azithromycin, Fidaxomycin
Lincosamides (-lin-): Clindamycin
Streptogramins (-prisitin): Dalfoprisitn/ Quinupristin
Oxazolodonones (-zolid): Linezolid, Tedizolid
Chloramphenicol
Name one aminoglycoside antibiotic that does not follow the aminoglycoside naming convention.
Amikacin
What are the two major subunits of the bacterial ribosome?
Large ribsomoal subunit and small ribosomal subunit
What are the 3 major steps in protein synthesis – what happens in each step?
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
Interferes with Initiation complex function (1 class):
Aminoglycosides (16S and 30S)
impairs Proofreading (1 class):
Aminoglycosides
interferes/ inhibits tRNA binding at the A site and / or peptide bond formation (6 classes
- Tetracyclines (16S on 30S)
- Glycylclines
- Lincosamides (23S on 50S)
- Streptogramins (23S on 50S)
- Oxazolidinones (23S on 50S)
- Chloramphenicol (23S on 50S)
block Exit of the polypeptide from the ribosome (2 classes)
Macrolides (23S on 50S)
Streptogramins
For the bactericidal class of protein synthesis-inhibiting antibiotics, what 3 types of processes are thought to contribute to the bactericidal effect?
- Formation of free radicals, which damage the cell
- Formation of holes in the cell membrane
- Formation of toxic aggregates inside the cell
What 2 steps are required for aminoglycoside antibiotics to reach their target site in gram negative bacteria?
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
How do each of the following impact cellular uptake of aminoglycosides in gram negative bacteria?
- 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
Are anaerobic bacteria susceptible to aminoglycoside antibiotics? Why or why not?
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
What is the basis for gram positive bacteria’s intrinsic resistance to aminoglycosides?
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
Compare the process of cellular uptake between aminoglycoside and tetracycline antibiotics.
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
Describe how bacteria alter (or protect) their antibiotic binding targets against aminoglycosides vs. tetracyclines
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
What is the function of a ribosomal protection protein?
Ribosomal protection proteins prevent tetracyclines from binding to the ribosome, allowing translation and protein synthesis to continue
Part of tetracycline resistance
Compare the resistance mechanisms by which bacteria limit concentrations of aminoglycosides vs. tetracyclines.
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
What is a TetR protein and what is its role in antibiotic resistance?
TetR prevents accumulation by increasing efflux which confers resistance to all tetracyclines
How do bacteria alter aminoglycosides to develop resistance to them (what’s the category of enzyme that is responsible)?
Transferase enzymes will chemically modify the aminoglycosides to develop resistance
Are glycylcyclines affected by the resistance mechanisms that affect other protein synthesis-inhibiting antibiotics?
Glycylcyclines are designed to avoid tetracycline resistance; not affected by ribosomal protection pumps (RPPs) or efflux pumps
Do aminoglycosides have activity against anaerobes? Why or why not?
Aminoglycosides do not have activity against anaerobes because there is no oxygen to drive the process
Which class of protein synthesis inhibiting antibiotics has particularly good activity against atypical pathogens like rickettsieae and Vibrio?
Tetracyclines
In addition to clindamycin (linocosamides) and gentamicin (aminoglycosides), what 3 classes of protein synthesis inhibiting antibiotics have particularly good activity against drug-resistant pathogens?
Streptogramins (-pristin): Dalforpristin / quinupristin
Oxazolidinones (-zolid): Linezolid / Tedizolid
Macrolides (-thromcin / -xomycin): Erythromycin /Clarithromycin / Azithromycin / Fidaxomycin
Which class is often used as eyedrops for eye infections?
Aminoglycosides: tobramycin and gentamicin
Which class is useful for COPD / asthma exacerbations?
Macrolides: due to anti-inflammatory and immunomodulating characteristics; erythromycin, clarithromycin, azithromycin, fidaxomycin
Which DRUG is used in inhaled form for treating bacterial infections in cystic fibrosis?
Tobramycin: treat P. aeruginosa in cystic fibrosis
Monobactam, aztreonam is used similarly
Which drug class, due to dependence on renal clearance, is dosed based on body weight and creatinine clearance and requires concentration monitoring?
Aminoglycosides
Which class has basically no oral absorption?
Aminoglycosides→ entire oral dose goes to feces; usually given IM or IV
Which 2 classes are only available by IV route?
Streptogramins (dalfopristin/quinupristin) and Glycylcyclines (tigecycline)
Which class cannot be taken with dairy products or antacids, and why?
Tetracyclines; dairy products impair absorption
- Multivalent cations and alkaline pH also impair absorption
Which class must be enteric coated to avoid destruction by stomach acid?
Macrolides
Which class is associated with nephrotoxicity and ototoxicity?
Aminoglycosides
Which class is associated with GI effects (and why?), hepatic toxicity, QT interval prolongation, and hearing loss?
Macrolides: GI effects (due to stimulation of gut motility via motion receptors), heart rhythm, hepatic toxicity, and drug interactions (P450 inhibitors)
Which class is associated with phototoxicity, bone / tooth toxicity, and hepatic toxicity?
Tetracyclines
Which class should not be administered to children or pregnant women, and why?
Tetracyclines
What are 5 advantages of docycyline vs. most other tetracyclines?
- 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
What two protein synthesis-inhibiting antibiotic agents have been associated with increased mortality risk?
Glycylcyclines (Tigecycline)
Which drug presents a risk for development of serotonin syndrome?
Linezolid (PO/IV); caution with antidepressants
Which drug is rarely used now, due to risk of bone marrow suppression, fatal aplastic anemia and gray baby syndrome?
Chloramphenicol; broad spectrum
Which protein synthesis-inhibiting antibiotic class is given with aminoglycosides, and why?
Combined with B lactams when needing to treat gram positive bacteria to create holes in peptidoglycan cell wall, allowing aminoglycosides to enter
Which protein synthesis-inhibiting agent is available as a 2-drug combination, and what is the advantage of combining the two?
Streptogramins: Dalfopristin / Quinupristin→ synergistic effects = rapidly bactericidal
