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86 Cards in this Set
- Front
- Back
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What are the 2 main components of protein synthesis in proks?
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1. Transcription
2. Translation |
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Which is a better target of antimicrobial agents?
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Translation
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Why is Translation a better target?
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Because the enzymes proks use for translation (70S ribosome) are different from euks; the enzymes in Transcription aren't different.
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What is the major difference between eukaryotic 80S ribosomes and Prokaryotic 70S ribosomes?
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How they look for initiating sequences on RNA to begin protein synthesis.
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What are the 4 antimicrobials that are protein synthesis inhibitors?
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-Linezolid
-Tetracycline -Aminoglycosides -Macrolides/Chloramphenicol |
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What does Linezolid inhibit?
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The initial binding of the 30S ribosome subunit to mRNA
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What does Tetracycline inhibit?
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The binding of fmet tRNA to the 30S ribosome
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What do the aminoglycosides inhibit?
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The further incorporation of amino acids into the growing polypeptide
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What do the macrolides and chloramphenicol inhibit?
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The functioning of the complete ribosomal complex.
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Is tetracycline bacteriostatic or cidal?
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Bacteriostatic
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And what is the mechanism of Tetracycline?
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Interferes w/ incoming aminoacyl t-RNAs binding to the ribosome by itself binding to PO4 residues on the 30s subunit.
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What does the synthesis of synthetic derivatives by modification of Tetracycline achieve?
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More lipophilic derivatives that are better absorbed.
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How selective is tetracycline?
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Not very - it inhibits protein synthesis in both proks and euks
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How come tetracycline is not toxic to eukaryotes then, but it is to prokaryotes?
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Proks use an energy-dependent transport system to accumulate tetracycline inside!
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What mechanism do euk cells use to take up tetracycline?
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Diffusion - it can go either way so doesn't accumulate.
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So where tetracycline is not selective in its inhibition of incorporating aminoacyl t-RNAs,
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It is selectively toxic in being actively taken up by proks versus passively diffused in euks.
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What are the 2 main mechanisms of RESISTANCE to tetracycline?
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1. Tetracycline efflux pumps
2. Mutations on the ribosome so it doesn't have interference with incoming aa-tRNAs |
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Which mechanism of resistance to tetracycline is more important?
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Development of efflux pumps - tetracycline still accumulates, but it then goes back out.
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What are the 2 main aminoglycosides called?
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-Kanamycin
-Gentamicin |
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Are the aminoglycosides bacteriostatic or cidal?
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Cidal
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What type of compounds are the aminoglycosides?
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Polar and polycationic
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What is the mode of action of the aminoglycosides?
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Inhibition of formation of the 30S initiation complex which decrease the rate of protein synthesis.
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What is the problem with Aminoglycosides?
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Limited permeability across outer membrane
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How do we get around the problem of limited permeability of Aminoglycosides?
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By using in combination with B-lactams
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What is the synergistic mechanism that allows B-lactams to help aminoglycoside entry?
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B-lactam disrupts the PG - lack of crosslinking means the cell wall is weak; so the aminoglycosides can get in better.
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What is the bacterial resistance mechanism to aminoglycosides?
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Covalent modification of the aminoglycoside itself
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What is achieved by covalently modifying aminoglycosides?
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Prevention of efficient entry of the drug into the bacterium.
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What are 3 types of covalent modification bacteria do to aminoglycosides?
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-Phosphorylation
-Adenylation -Acetylation |
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How do the bacteria modify aminoglycosides?
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They have enzymes that do it.
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What antimicrobials inhibit peptide bond formation during protein synthesis?
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Macrolides
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What is the macrolide produced by Streptomyces?
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Erythromicin
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Is erythromycin bacteriostatic or cidal?
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Static, but cidal at high concentrations.
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What part of protein synthesis does Erythromycin inhibit?
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-Not actually formation of peptide bonds, but rather:
-Movement of the deaminoacyl t-RNA from the P site to allow for translocation |
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What mechanism of resistance do some bacteria have to Erythromycin?
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Methylation of the rRNA to prevent erythromycin from binding and preventing translocation.
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Why arent there more antimicrobials that inhibit DNA function w/ enough specificity to be used clinically?
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Because prokaryotic DNA synthesis is identical to eukaryotic DNA synthesis
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What is one antimicrobial that is an inhibitor of DNA function?
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Metronidazole
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What is metronidazole used to treat?
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Anaerobic infections - Bacteroides
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What is unique about Metronidazole?
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It is a prodrug that requires activation by the bug before it works as a drug.
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What activates Metronidazole?
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An anaerobic environment
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What does activated Metranidazole do?
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Interchelates into DNA to prevents DNA synthesis.
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What drug inhibits DNA gyrase?
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Quinolone
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So the 2 main DNA inhibitors are:
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-Metranidazole
-Quinolone |
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What is a 1st generation quinolone?
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Naladixic acid
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What is a 2nd generation quinolone?
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Ciprofloxacin
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What is the mode of action of naladixic acid?
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Selective inhibition of BACTERIAL DNA gyrase, but NOT mammalian gyrase.
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Why isn't Naladixic acid prescribed in clinics?
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-Narrow spectrum
-Rapid selection for resistance |
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What is Cypro?
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A FLUORINATED quinolone
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What is Cypro especially useful for?
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Multi-drug resistant Staphs, Enterococci, and Pseudomonas
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What is unfortunate in what has happened with Cipro?
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It was pulled off the list as effective against Anthrax, and now it's floating around and resistance is increasing.
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Why haven't we seen much resistance to the 2nd generation fluoroquinolones develop?
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Because bacteria can't really tolerate mutations in DNA gyrase beyond single point mutations.
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How do metabolic analogues work as antimicrobial agents?
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By acting as competitive inhibitors of natural substrates.
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How do bacteria overcome metabolic analogues?
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By increasing the concentration of the natural substrate.
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In what pathway are metabolic analogues mostly used as antimicrobial agents?
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The THF pathway
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What is the THF pathway?
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A two enzyme pathway for the synthesis of THF
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What is THF used for?
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Introducing 1-C groups into biosynthetic precursors.
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What is Step 1 in THF biosynthesis?
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Complex para-Aminobenzoic Acid (pABA) with Pteridine to make Dihydropteroic acid
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What is special about the first step in THF biosynthesis?
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Only prokaryotes have it
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What antimicrobial metabolic analogue inhibits the first step?
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Sulfonamides
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What happens once the Dihydropteroic acid is formed?
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Conversion to Dihydrofolic acid (FH2) and then THF (FH4).
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What are the antimicrobial metabolic analogues of FH2?
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Trimethoprims
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So the 2 metabolic analogues that inhibit THF biosynthesis are:
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-Sulfonamides
-Trimethoprim |
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How are the sulfonamides selective in being toxic to prokaryotes?
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Eukaryotes lack that step
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How is Trimethoprim selective in being toxic to prokaryotes?
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The bacterial reductase that acts on FH2 has much higher affinity for Trimethoprim than eukaryotic reductase does.
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How are the sulfonamides and trimethoprim used clinically?
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Synergistically -> Bactrim
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What are 4 reasons for using antimicrobial drugs in combo?
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1. Best guess - need to treat meningitis or bacteremia quick
2. Mixed infections 3. Delay emergence of resistant mutants 4. Synergy achieves better results |
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In what infection is it very important to use combinations of drugs to prevent emergence of resistance?
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Mycobacteria
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What are the 3 examples of Synergy where 2 drugs are better than one?
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Trimethoprim + Sulfomethoxazole
Penicillin + Aminoglycosides (allows better cell uptake) Clavulinic acid + B-lactams (inhibits b-lactamases) |
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What is an example of INNATE resistance to antimicrobials?
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Mycoplasma pneumoniae - lacks a cell wall so you can't treat it with cell wall inhibitors.
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What are bacteria that don't have dihydrofolate synthetase resistant to?
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Sulfonamides
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What are the 2 main types of genetic resistance to antibiotics?
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1. Mutations
2. Genetic exchange |
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Are mutations very commonly the basis for development of resistance? Why?
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No - because they're low frequency and typically low level resistence results.
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Except what antibiotic resistance DID develop via mutations?
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Quinolone resistance (not so much the fluoroquinolone)
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What genetic resistance is more daunting?
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Genetic exchange
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What are the 3 types of Genetic exchange?
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1. Conjugation (mating)
2. Transduction (phage) 3. Transformation (of DNA) |
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How does multi-drug resistance develop?
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Plasmid transfer and selection for resistance to one drug allows the same bug to develop resistance to other drugs.
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What are the steps in developing drug resistant bacteria?
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1. Random event of DNA mutation occurs
2. The drug selects for drug resistant bacteria (we give the drug to patients intending eradication, the bug lives) |
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What is NOT the mechanism whereby drug resistant bacteria develop?
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Adaptation
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So the 3 major mechanisms of microbial resistance to antibiotics are:
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1. Modification of antibiotic
2. Modification of target 3. Drug efflux system |
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What 2 drugs are the targets of modification of themselves?
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Penicillin (b-lactamase)
Gentamicin (bacterial enzymes covalently modify it) |
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What 2 drugs are resisted by modifications of their targets?
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1. Erythromycin (bacteria methylate rRNA)
2. Vancomycin (bacteria modify the PG) |
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What drug is resisted by drug efflux systems?
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Tetracycline
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What is the general strategy for develping new antimicrobial drugs?
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MODIFICATION of pre-existing drugs
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Why aren't new classes of drugs being developed?
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-Expensive
-Rapid antibiotic resistance development makes it a waste of time. |
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What is the latest new drug that was brought to clinic?
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Linezolid
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What does Linezolid inhibit?
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Early steps in protein translation
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What is sad about linezolid?
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It already has resistance developed.
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