patho exam 2 part 2

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patho exam 2 part 2
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  1. Transpeptidases and other proteins involves in catalyzing the cross-linking process and are often referred to as ... ?
    Pencillin Binding Proteins (PBP's) -targets for antibiotics
  2. What are autolysins job?
    -cut PG w/out insertion of new material leading to breaks and cell lysis
  3. Vancomycin is an example of ... ? What is vancomycin's job?
    a β-lactam type.

    -binds to PG precursors not PBP(penicillin-binding protein)
  4. What is the last barrier against some Gram (-) pathogens, Sty. aureus and Enterococcus (VRE!) BUT cannot penetrate Gr (-) outer membrane, large bulky molecule that cannot diffuse thru outer-membrane porins is...
    Vancomycin
  5. Vancomycin is a glycopeptide that binds to _______________ in the PG precursor when it is transferred out of the cell through the membrane.
    D-ala-D-ala
  6. What's a problem associated with antibiotics?
    -there are allergic rxns to penicillin and related β-lactams
  7. How do allergic rxn to penicillin work?
    -antibiotic binds convalently to a blood protein, & immune system now sees this hybrid as foreign and mounts a respones to it

    therefore, memory cells are pried for subsequent exposues whether the antbiotic is bound to the protein protein or not. 

    --alternative β-lactam have been developed that don't trigger same allergic response.
  8. What are Protein Synthesis Inhibitors essential for ?
    -structural components and enzymes.

    -ribosomes take an mRNA molecule and translate it into a protein.

    EXCEPTION: mupirocin --> these inhibitors bind to ribosomes!
  9. What does Tetracycline do ?
    -interfere with attachment tRNA to mRNA - ribosome complex.
  10. Tetracyclines are produced by..?
    several members of Streptomyces.

    -4 fused cyclic 6-membered rings (NAPTHACENE RING SYSTEM)

    -bind to 30S ribosomal subunit prevents binding of amino acid-bearing tRNA.
  11. Pro of Tetracycline...
    -one of the LEAST toxic antibiotic (oral administration // treatment of acne)
  12. Cons of Tetracycline....
    overprescription for acne (bc its least toxic), livestock growth addition 

    widespread resistance 

    derivatives are still important - Lyme Disease and STDs.

    extremely large # of derivatives can be synthesized. 
  13. Tetracycline has a lot of derivatives!
    4 R-groups and if you use 5 reagents to crete derivatives...

    5 x 5 x 5 x 5 = 625 derivatives 

    test each 1 for diff properties and activities
  14. Targets for DNA replication...
    • Quinolones 
    • bacteriocidal
    • synthetic cmpds 
    • interact w/DNA gyrase
    • prevent supercoiling of DNA 
    • can penetrate macrophages and PMNs to kill intracellular pathogens
  15. The Nalidixic Acid prototype is ?
    the Fluoroquinolone derivatives--Ciproflaxin, more soluble 

    treat Gr (-) & (+)

    Protective resident flora of oral cavity, GI tract and vagina are not greatly affected
  16. Metroniazole interferes with...?
    -with DNA synthesis, not by unhibiting an enzyme but makes breaks in DNA .

    -requires activation I- via bacterial housekeepig proteins flavodoxin and ferredoxin (not precent in aerobes)

    -nitro group of antibiotic is reduced to make the active form that interacts with DNA and nicks DNA strands.
  17. What does Metronidazole treat?
    ulcers and stomach inflammation - Helicobacter pylori

    • Anaerobic pathogens that are resistance to other antibiotics. 
  18. Problem of Metronidazole...
    single mutation in target = rapid resistance!
  19. Metronidazole is used for...
    UTI

    Penicillin resistant- Bacillus anthracis

    Beef & poultry industry to prevent respiratory diseases and food born pathogens (large # of animals/birds in one area - rapid spread of infection - over use?)
  20. Azithromycin (macrolide) is a..?
    new antibiotic that treats STDs, chlamydia & gonorrhea

    (1 or 2 closely timed doses) - easier patient monitoring...

    -prob w/ other long term, 6-9 months treatment regimes (TB) full courses are not completed -- leads to RESISTANCE.
  21. What is used to treat middle ear infections, tonsillitis, throat infections, laryngitis, bronchitis, pneumonia, typhoid, and sinusitis ?
    Azithromycin
  22. What is one of the world's best-selling antibiotics?
    ZPAK, but expensive.

    -impoverished populations (inner city clinics and developing countries) do not have access.
  23. Who discovered ZPAK in 1980 ?
    -A team of researchers at the Croatian pharmaceutical co.

    -patented in 1981

    --Pfizer's scientist found it while going thru patent documents, so in '86 Pliva and Pfizer signed a licensing agreement giving Pfizer exclusive rights for sale of ZPAK in Western Europe and U.S.
  24. Antiviral Compounds tend not to be ______ spectrum as with some antibiotics..
    BROAD spectrum... bc of its simple structure

    • viruses are not free living 
    • use host cell biosynthetic machinery to reproduce
  25. Antiviral cmpds do not have as many targets to kill....
    have to be cautious when trying to kill target since its attached to host...

    • viral proteins that mediate attachments to cell 
    • virus proteins involved in copying of viral genome 
    • viral surface coat
  26. Amantadine is a .... ?
    an anti-influenza drug
  27. What's the normal process for Amantadine?
    Virus attaches to host cell, triggers cell to take it in w/in a vesicle 

    in the cell it's acidic (human enzymes) coat proteins strip off releasing nucleic acid to become integrated into host genome.
  28. What does Amantadine do ?
    stabilizes viral proteins and nucleic acid (RNA) so nucleic acids not released to join host genome. Not 100% effective but can significantly reduce severity of infection. 

    -imp. for elderly, since flu virus is the most rapidly mutating.
  29. Acyclovir is used for ?
    herpes simplex virus type II - 1980s STD

    cold sores

    -virus (DNA genome) replicates in epithelial cells of mucus membranes of mouth and genital tract producing lesions. 

    -as immune sys kicks in, virus then infects nerve cells and become quiescent. -at some later time a trigger (stress?) causes virus to re-enter epithelial cells and become active again 

    (dormant/inactive)
  30. What does acyclovir interfere?
    interferes with viral DNA replication...BUT FIRST, needs to be activated by the viral enzyme thymidine kinase

    •  But, only works in actively growing virus in epithelial cells; not in the inactive stage present in nerve cells.
  31. Antifungal Compounds targets...
    some broad spectrum cmpds that targets enzymes that syntheses fungal form of cholestrol, ergosterol.
  32. Inhibitor of ergosterol synthesis is?
    Tolnaftate
  33. Dermatophytes is....?
    athlete's foot, tinea cruris (joch itch-men and women) ringworm and nail infections
  34. Griseofulvin is... ?
    thought to inhibit protein complexes that make microtubules involves in cell division (mitosis)
  35. Examples of Skin and Nail infections
    (these are antifungal cmpds)

    -dermatophytes 

    -griseofulvin
  36. Agents effective against Candidiasis....
    Candida albicans - part of the normal flora of mouth, throat, and vaginal tract 

    -range 4rm superficial, minor skin infections, oral thrush and vaginitis, to systemic and potentially life-threatening diseases. 

    -Candida infections of the latter category are also referred to as candidemia and are usually confined to severly immuno-compromised persons, such as cancer, transplant, and AIDS patients as well as non-trauma emergency surgery patients.
  37. Azoles are diflucan, ketoconazole that inhibit...
    ergosterol synthesis and destabilizes membrane (slow growing, slow acting) and interferes w/ nutrient take up

    (similar to vancomycin on PG)
  38. Polyenes do what?
    bind ergosterol and form channels in membrane.
  39. Ergosterol is structurally similar to cholesterol and therefore ....
    binds to this although to a lesser degree
  40. Flucytosine is an example of...
    antifungal cmpd
  41. Nucleotide analogue? -Flucytosine
    incorporated into RNA and disrupts transcription by inhibiting thymidylate synthase important in DNA synthesis.

    -chemical rxns change causing host to die
  42. Because of its relatively weak action ____________ is often used with another antifungal drug to increase effectiveness of treatment.
    flucytosine
  43. Antibiotic Cocktails are ?
    a treatment when you need to use a 2nd / multiple antibiotics because of resistance to bacteria.

    -over prescription, out of control, even minor aliments treated, abuse in agriculture
  44. Cost of antibiotic resistance...
    21% of S. aureus infections were caused by MRSA strains 

    add'l cost per patient=$2500

    longer hospital stay=$3700 per patient

    • -vancomycin: more expensive than pervious treatments 
    • -isolate patients 
    • -mortality rate 21%
  45. What happens when vancomycin-resistant strains appear?
    obtain resistance gene 4rm another bacterium (gene transfer)
  46. Vancomycin resistant enterococci ...
    VRE (1986) - vancomycin and avoparcin used widely in animal feed
  47. VRE banned in '96 and removal of selective pressure led to...
    VRE-(+) samples decreased 4rm 100 - below 25%

    Human carrier rate dropped 4rm 12 - 3%
  48. Mechanism of Resistance...
    • Restricted access to target
    • Enzymes that inactivate the antibiotic 
    • Modification / protection of the antibiotic target
    • Failure to activate antibiotic
    • Modification to a biochemical pathway
    • Lack of target structure
  49. Many resistance mechanisms are mediated by.....
    bacterial house-keeping genes.

    ex: enzymes that inactivate penicillin are related to / evolved from those that carry out cross-linking of PG.
  50. Bacteria may adapt the target of an antibiotic to become a ____________ against the antibiotic.
    weapon
  51. Examples of restricted access to target...
    -outer membrane porins 

    -reduced uptake across cytoplasmic membrane 

    -efflux pumps
  52. Outer Membrane Porins
    (ex. of restricted access to target)

    -penicillin binding protein targets are present in cytoplasm 

    -Gram (-) outer membrane can act as barrier. Genetic mutations of the porins can further resist entry 

    -Vancomycin too bulky to cross
  53. Reduced uptake across cytoplasmic membrane
    (ex restricted access to target)

    -may be transporter mechanisms involved 

    -when grown anaerobically some bacteria become much more resistant. --not as much energy available
  54. Efflux pumps
    (ex of restricted access to target)

    -bacteria pump out the antibiotic cytoplasmic membrane protein that catalyzes energy-dependent transport of tet', out of cell. 

    ex: tetracyclines


    these pumps appears to be widespread, found in both Gram types and for several classes of antibiotics
  55. β-lactamases
    EX: enzymes that inactivate the antibiotic.

    -major mech in Gr. (-), secreted into periplasmic space, enzyme cleaves the β-lactam ring (C-N) and inactivates the antibiotic.

    -Gr (+) secreted into extracellular fluid = gets diluted (not good) bc require higher levels to be produced to achieve required concentration
  56. Strategies for enhancing antibiotic efficacy?
    Duel administration w/ β-lacatamase inhibitor

    sulbactam

    clavulanic acid 

    irreversible binding

    -there is a 2nd class of β-lactamases that aren't inhibited and cmpds haven't been found that inhibit these.
  57. β-lactam + β-lactamase ⇾
    β-Lactam inactivated = no effect on bacteria
  58. β-Lactam + clavulanic acid + β-lactamase ⇾
    Inactivated β-lactamase ⇾ β-Lactam unaffected ⇾ KILLS bacteria
  59. Aminoglycoside antibiotics
    (ex of modifying enzymes)

    -rather than cleaving a bond or removing an active group modifying enzymes add groups ) phosphoryl, adenyl, or acetyl groups)

    -thought to be located on the outside of the cytoplasmic membrane or secreted onto extracellular fluid.
  60. β-lactams (ex: methicillin, penicillin, and other penicillin-like antibiotics)
    (ex of modification or protection of antibiotic target) 

    -binding specificity of penicillin-binding proteins is altered (lowered)

    -most common in Gr (+) and currently causing most concern clinically.
  61. mecA is a...?
    resistance gene; resistance in Sty. aureus 

    -encodes a mutant β-lactam binding proteins that replaces the norman transpeptidase and allows peptidoglycan cross-linking to occur, even in presence of antibiotic. 

    -therefore, target for antibiotic is no longer present .
  62. Glycopeptides
    ex: vancomycin: prevents cross-linking of PG by binding to D-ala-D-ala of the muramyl-peptide 

    resistant bacteria replace this with D-ala-D-lactate. (vancomycin cannot bind to this)
  63. 3 enzymes involved for resistant phenotype.
    vanH : encodes a lactate dehydrogenase that makes lactate 4rm pyruvate 

    vanA / vanB : encodes a ligase that makes D-ala-D-lactate 4rm D-ala and D-lactate .

    -vancomycin cannot bind to D-ala-D-lactate

    BUT original dipeptide can still be incorporated and must be removed.
  64. 3rd gene vanX codes for an enzyme that __________________________ until all the D-ala-D-ala is replaced.
    cleaves 1 D-ala 4rm D-ala-D-ala but not from D-ala-D-lactate until all the D-ala-D-ala is replaced.

    -most complex resistance mechs known, requires a large expenditure of energy 4rm bacteria.
  65. Origin of resistance...
    • lateral gene transfer 4rm naturally resistant Lactobacillus species that do not have D-ala-D-ala as part of their muramyl dipeptide?
    • transfer 4rm vancomycin-producing bacteria 

    -more efficient to obtain 4rm other sources than trial and error by organism itself
  66. Resistance to tetracyclines..
    ribosomal protection conferred by a cytoplasmic protein that protects ribosome.

    -mechanism is unclear, but no covalent modification of the ribosome is observed. 

    -this protein shares a high AA similarity in its amino terminal w/ bacterial elongation factors involved in protein synthesis. --probably that this method of protection evolved 4rm EF(elongation factor) .
  67. Failure to activate antibiotic....
    ex: metronidazole 

    -requires activation - by housekeeping protein: flavodoxin/ferredoxin

    -mutations that lower expression of flavodoxin may be involved. 

    • -used to treat ulcer--resistance in H. pylori
  68. What is resistance?
    bacteria continue to grow in presence of antibiotic.
  69. Tolerance is... ?
    -bacteria stops growing in present of antibiotic, but when antibiotic is removed, bacteria can recover & multiply
  70. Antibiotic Tolerance is...?
    imp in biofilms and medical implants (catheters, heart valves) UTI, and lungs of cystic fibrosis patents.
  71. What appears to be non-growing?
    antibiotic tolerance
  72. % of bacterial cells are dormant, called ___________
    Persisters & contribute to high levels of tolerance.
  73. Genome plasticity.....
    responds to diff environmental stresses (antibiotic tolerance)

    -reduce metabolic production of antibiotic targets
  74. Antibiotics that inhibit cell wall synthesis are ___________ because the bacterial autolysins work to degrade pre-existing PG.
    bactericidal


    but, bacteria that can prevent their autolysins destroying their PG or can survive in the body without a cell wall can avoid being killed. 
  75. Vancomycin tolerance in Str. pneumoniae (bacterial pneumonia and meningitis)
    • normally 2-component regulatory sys, (vncR [represses autolysis]; vncS [phosphorylates VncR]) that controls autolysis
  76. VncS can _____________ VncR so allowing autolysins to be made when new PG is required.
    also dephosphorylate 
  77. In resistant strain of ________________, mutations have abolished production of VncS (controls autolysis)
    S. pneumoniae

    therefore, another molecule must be involved; although PG is no longer produced,  bacteria survive bc they do not lyse.
  78. E.coli strains in kidney infections is an example of ?
    Antibiotic Tolerance.
  79. What happens when E.coli strains create kidney infections?
    -kidneys filter blood and excrete waste in urine (salt conc in kidney = higher than in other tissues)

    -penicillin stops cell wall synthesis and autolysins degrade the existing PG. 

    -BUT, osmotic strength of fluid prevents bacteria 4rm lysing. 
  80. what prevents bacteria from lysing?
    Osmotic strength of fluid
  81. L-forms are.... ?
    mutant bacterial strains lacking cell wall
  82. MRSA
    methicillin resistant Staphylococcus aureus (UK 1960s)
  83. VRE
    vancomycin resistant Enterococcus (France 1986 USA 1989)
  84. Multiple resistant M. tuberculosis 
    intracellular pathogen

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