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Antimicrobial Therapy and Prophylaxis (2023) > Antibiotics, Antibacterials & Resistance mechanisms > Flashcards

Antibiotics, Antibacterials & Resistance mechanisms Flashcards

1
Q

What are the general mechanisms of antimicrobial resistance?

A
  1. drug target alteration
  2. drug target overexpression
  3. reduction of intracellular accumulation of the drug (efflux pump)
  4. alternate structures and metabolites
  5. activation of cellular stress pathways
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2
Q

Definition antibacterial

A

agents selective acting against prokaryotes

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3
Q

Definition antibiotics

A

antibacterials produced by a living organism

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4
Q

Name the first antibiotics/antibacterials

A
  1. antibiotic: Pyocyanase (1890)
  2. antibacterial: Salvarsan (1910)
  3. ß-lactam: penicillin (1928)
  4. Sulfadrug: Prontosil (1932, antibacterial)
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5
Q

What makes an ideal antibacterial?

A
  • high specificity
  • bactericidal
  • high therapeutic index (ratio between lethal (animal)/toxic (human) and therapeutic dose)
  • various routes of administration
  • good absorptionsfähiges and distribution
  • no resistances
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6
Q

Descriminate between broad and narrow spectrum antibacterials

A

broad: active against gram- and gram+
narrow: limited activity and are primarily useful against particular species

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7
Q

Describe the molecular structure of the different antibacterial classes

A
  • ß-lactams: ß-lactation ring
  • aminoglycosides: aminomodified sugars and different sidechains
  • sulfonamide: amide with sulfure instead of oxygen in main chain
  • glycopeptides: glycosylated cyclic or polycyclic peptides
  • quinolones:
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8
Q

ß-lactams

A
  • interfere with cell wall synthesis
  • lactam is a cyclic amide
  • structural analog to natural D-Ala-D-Ala -> covalent inhibition of DD-Transpeptidase (PBP) -> weakens cell wall
  • ~50 different in use
  • all are bacteriocidal and non toxic + relatively inexpensive
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9
Q

What do autolysins do?

A
  • membrane-associated enzymes that break bonds between/within peptidoglycans
  • important for cell wall turnover and shape
  • trigger cell lyses in combination with inhibited cell wall synthesis
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10
Q

Explain the downside of antibiotic treatment

A

the use of antibiotics/antibacterial can lead to selection of resistances, already present in some microorganisms of the population, especially if the drugs are not used in a high enough dose

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11
Q

Resistances against ß-lactams

A
  1. ß-lactamase:
    - hydrolysis of ß-lactam ring -> compound is inactivated
    - sensitive bacteria are not fast enough in cleaving the ß-lactam ring if ß-lactamases are present
  2. Mutation in PBP
    - amino-acid replacement in the active site -> diminished affinity for ß-lactam
    - MRSA encode for special PBP-2 variant PBP-2A -> no efficient shut down
    • PBP-2 and PBP-2A cooperate in transpeptidation and transglycosydation
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12
Q

Penicillin alternative?

A
  • Cephalosporins
  • same mode of action
  • broader spectrum than penicillins
  • more resistant to ß-lactamases
  • instead of Thiazolidine (5) next to ß-lactam ring they have a Dihydrothiazine (6) ring
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13
Q

What can treatment with ß-lactams improve?

A
  • ß-lactamase inhibitors in combination therapy
  • other classes of antibiotics
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14
Q

Glycopeptides

A
  • molecules produced by Actinobacteria
  • glycosylated cyclic/polycyclic peptides
  • last resort in MRSA and MDR Strep. pneu.
  • only against gram+
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15
Q

Resistances against glycopeptides

A

vanA-type vancomycin resistance:
- last peptide switches -> D-Lac instead of D-Ala -> no binding of vancomycin
- S. aureus acquired gene horizontally from VRE

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16
Q

Fosfomycin

A
  • broad-spectrum antibiotic
  • cell entry through glycerophosphate transporter
  • inhibits first enzyme of cell wall biogenesis/peptidoglycan biosynthesis -> MurA
  • alkylating cysteine residue in active site
17
Q

Resistance to fosfomycin

A
  • in S. aureus
  • fosfomycin modification (phosphorylation) -> FomA
  • fosfomycin hydrolysis (FosA, FosB, FosX)
  • modification of MurA
  • MurA overexpression
18
Q

Tetracyclines

A
  • Naphtacene core
  • broad-spectrum bacteriostatic antibiotic
  • primary binding site (Tet-1) overlaps with a-tRNA in A-site, interaction mainly with 16S rRNA
  • secondary binding sites (Tet-2) also found
19
Q

Resistances to Tetracyclines

A

TetA/TetR:
- efflux pump, TetA is gene, TetR is regulator
- like lac-operon TetA is only transcribed when TetR is bound to Tet and doesn‘t inhibit TetA promotor

also ribosomal protection, degradation and rRNA mutations

20
Q

Aminoglycosides

A
  • mainly against gram- bacteria
  • bactericidal
  • natural and synthetic
  • suffix: -mycin -> from Streptomyces
  • suffix: -micin -> from Micromonospora
  • often used as last resort
21
Q

Aminoglycosides - mode of action

A
  • bind to A-site (incorrect proofreading) or between A- and P-site (blocking of translocation) of ribosome
  • ultimately they lead to mistranslated and therefore misfolded proteins
  • misfolded proteins in membrane disrupts cell membrane integrity -> even more drug uptake
22
Q

Resistances against Aminoglycosides

A
  • rRNA-modification by Methyltransferase
  • (point-)mutations of ribosomal proteins (S12 peptide) -> no aminoglycoside binding
23
Q

Macrolides

A
  • lactone ring bonded to sugar
  • 20% of used antibiotics are macrolides
  • Erythromycin is broad-spectrum antibiotic targeting 50S subunit of ribosome
24
Q

Macrolides - mode of action

A
  • partial inhibition of protein synthesis -> leads to imbalance in protein synthesis
    -> imbalance in proteosome disrupts metabolic function at all levels
  • block of ribosomal peptide exit channel
25
Q

Resistances to Macrolides

A
  • mutation in L4 and L22 -> L22 is flexible -> exit tunnel big enough for peptide
  • efflux pumps (Mef & Msr)
  • ## modifications at 23S rRNA
26
Q

Glycopeptides - mode of action

A
  • bind to D-Ala-D-Ala dipeptide and block PBP crosslinking activity -> steric inhibition
27
Q

Tetracyclines - mode of action

A
  • steric hindering of incoming t-RNA
  • prokaryotic specificity: uptake via Omp (outer membrane proteins) only possible in prokaryotes; Tet is bound to metal at pH 7
28
Q

Quinolones

A
  • all bactericidal
  • broad-spectrum
  • small hydrophilic molecules -> easily diffuse through membranes
29
Q

Quinolone target

A

DNA-gyrase (topoisomerase type II) and topoisomerase IV

30
Q

What do topoisomerases do?

A
  • twist cyclic DNA to make them more compact
    Lk = Tw + Wr
  • type I: produce transient nicks (single strand) -> Lk change by 1 or n
  • type II: produce transient breaks (double strand) -> Lk change by +/- 2
    - ATP-dependent; DNA gyrase and Topo IV
31
Q

Resistances to Quinolones

A
  • modifications of quinolone binding site of target
  • transferable plasmid-borne resistance: gene qnr expresses a pentapeptide repeat protein which blocks quinolone binding site without inhibition
  • efflux proteins
32
Q

Rifampicin

A
  • bactericidal
  • primarily targets gram+ (some gram-)
  • in combination used to treat TB and MRSA
33
Q

Rifampicin - mode of action

A
  • binds 2-5 nucleotides away from catalytic center of polymerase -> blocks elongation
  • binding only possible if no nucleotides already occupy the space
34
Q

Resistances to Rifampicin

A
  • spontaneous mutation in gene expressing ß-subunit of RNA-Pol -> loses affinity
  • transferable plasmid: enzyme that inactivates rifampicin by transferring an ADP-ribosyl
35
Q

Sulfonamides

A
  • against Staph., Strep., and E. coli
  • rarely (3%) can have severe side effects (17% fatality)
  • where the first produced antibiotics
36
Q

Sulfonamides - mode of action

A
  • inhibition of folic acid (Vit B9) synthesis by substrate competition
  • analog of p-Aminobenzoic acid (PABA) -> part of folic acid synthesis
  • humans don‘t have that synthesis pathway (no own production of folic acid/Vit B9)
37
Q

Resistances to Sulfonamides

A
  • mutational changes of target enzyme dihydropteroate -> limited binding
  • natural resistances due to lack or overexpression of dihydrofolate reductase
  • development of alternative pathway -> active uptake
38
Q

Name the ways bacteria can acquire resistances

A
  • Transformation (free DNA)
  • Transduction (phage)
  • Conjugation (plasmid transfer)
  • Transposition

Antimicrobial Therapy and Prophylaxis (2023) (13 decks)

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