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Block 1 - Week 4 > Introduction to antibiotics > Flashcards

Introduction to antibiotics Flashcards

1
Q

What is a key feature of the Beta-Lactam antibiotic structure?

A

The beta-lactam ring

This ring has to be intact in order for the drug to be active

Also has thiazolidine ring

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2
Q

How do beta-lactam antibiotics kill bacteria?

A
  • As D-Ala-D-Ala analogs, they covalently bind to specific receptors (penicillin-binding proteins, aka PBPs)
  • Act as competitive inhibitor to transpeptidase
  • Also activate autolysins (bacterial enzymes that remodel/breadk down cell wall) –> Causes lesions in cell membrane and wall
  • Thus inhibiting bacterial cell wall synthesis
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3
Q

What are the three main mechanisms microbes develop antibiotic resistance?

A
  1. ) Production of drug-inactivating enzymes
  2. ) Change structure of receptor or binding site (decrease affinity for the drug)
  3. ) Changes in drug permeation and transport (decreasing drug accumulation)
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4
Q

Bactericidal agents

A

Kills the bacteria

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5
Q

Bacteriostatic agents

A

Stop bacteria from reproducing while not necessarily killing them

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6
Q

Why can bacterial cells survive in water?

A

The bacterial cell wall prevents lysis from high osmotic pressure. If a human cell was placed in water the osmotic pressure would cause it to lyse.

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7
Q

Porin

A

Channels on proteins that are permeable to hydrophilic substances such as B-Lactams

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8
Q

What is peptidoglycan polymer chain?

A

The basic unit of the cell wall

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9
Q

What does the peptidoglycan polymer chain consist of?

A

Polysaccharides with alternating aminohexoses:

  • N-acetylmuramic acid
  • N-acetylglucosamine
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10
Q

What does the peptidoglycan polymer chain terminate in?

What is the relevance of this?

A

D-Alanine-D-Alanine + pentaglycine bridges

This is where cross-linking occurs, and B-lactams are structural analogs of the D-Ala-D-Ala substrate and therefore acts as competitive inhibitor

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11
Q

Transpeptidation in bacterial cell wall formation

A

A transpeptidase enzyme links the pentaglycine bridge of one peptidoglycan to the D-Ala-D-Ala of another forming the cross-link

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12
Q

What mechanisms can make a bacteria resistant to penicillin?

A
  1. ) Inactivation via plasmid-mediated B-lactamase (penicillinases) –> Most staphylococci and many gram (-) organisms
  2. ) Modification of PBPs to decrease affinity for drug –> MRSA, MRSE, and PRSP
  3. ) Impaired penetration to target PBPs (changes in porin structure in gram (-) rods)
  4. ) Presence of efflux pump
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13
Q

Cephalosporin main structure

A

B-lactam ring

Dihydrothiazine ring

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14
Q

Cephalosporin class

A

Class of B-lactam antibiotics

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15
Q

Cephalosporin mechanism of action

A
  • Very similar to penicillin
  • D-Ala-D-Ala analogs, bind to PBP, inhibit transpeptidase
  • Activate autolysins
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16
Q

Monobactams

A
  • Has monocyclic B-lactam ring (B-lactam class of Abxs)
  • Drug name: Aztreonam
  • Binds to a specific PBP (PBP3)
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17
Q

Carbapenems

A
  • Synthetic B-lactam drugs structrually related to penicillins (B-lactam ring + 5-membered penem ring)
  • Common drugs: Imipenem, Meropenem, Doripenem, and Ertapenem
  • Resistant to most B-lactamases, but susceptible to metallo-B-Lactamase
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18
Q

B-lactamase inhibitors (basics)

A
  • Resemble B-lactam drugs
  • Inhibit B-lactamases by competitive inhibition
  • Have low antibiotic activity when used alone
  • Used with penicillins in fixed combinations
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19
Q

What are the main B-lactamase inhibitor/penicillin combinations?

A
  • Timentin: Ticarcillin + Clavulanic acid
  • Augmentin: Amoxicillin + Clavulanic acid
  • Unasyn: Ampicillin + Sulbactam
  • Zosyn: Piperacillin + Tazobactam
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20
Q

What class of antibiotics do penicillins and cephalosporins belong to?

A

B-Lactams

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21
Q

What penicillin drug and B-lactam inhibitor make up Augmentin?

A

Amoxicillin + Clavulanic acid

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22
Q

What penicillin drug and B-lactam inhibitor make up Unasyn?

A

Ampicillin + Sulbactam

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23
Q

What penicillin drug and B-lactam inhibitor make up Zosyn?

A

Piperacillin + Tazobactam

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24
Q

What penicillin drug and B-lactam inhibitor make up Timentin?

A

Ticarcillin + Clavulanic acid

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25
Q

Vancomycin

A
  • No B-lactam ring (doesn’t bind to PBPs)
  • NOT susceptible to B-lactamases
  • Binds firmly to D-Ala-D-Ala terminus of peptidoglycan pentapeptide, thereby blocking the Transglycosylase Enzyme, thus blocking peptidoglycan elongation and cross-linking
  • Also damages cytoplasmic membranes
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26
Q

Penicillin-Binding-Proteins (PBPs)

A
  • Involved in final stages of peptidoglycan synthesis
  • Are the target of beta-lactam antibiotics
  • Belong to a group of enzymes called transpeptidases
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27
Q

What is the mechanism of Vancomycin resistance?

A
  • Terminal D-Ala is replaced by D-lactate –> Decreases affinity of vancomycin
  • Plasmid-mediated changes in permeability to the drug
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28
Q

What are come common Vancomycin-resistant bacteria?

A
  • VRE: Vancomycin-resistant enterococci

- VRSA: Vancomycin-resistant staphylococcus aureus

29
Q

Daptomycin

A
  • Structure: novel cyclic lipopetide with spectrum similar to vancomycin
  • Disrupts multiple aspects of bacterial cell membrane (creates holes that leak ions, causing depolarization)
30
Q

Fosfomycin

A
  • Antimetabolite inhibitor of cytosolic enolpyruvate transferase –> prevents the formation of N-acetylmuramic acid (precursor of peptidoglycan chain)
31
Q

Cycloserine

A

An antimetabolite that blocks the incorporation of D-Ala into the pentapeptide side chain of the peptidoglycan

32
Q

Bacitracin

A

A peptide antibiotic that interferes with a late stage in cell wall synthesis in gram (+) organisms

33
Q

What is the mechanism of action of Ribosomal Antibiotics?

A

Inhibit protein synthesis by binding to and interfering with ribosomes

34
Q

List of Ribosomal antibiotics

A
  • Spectinomycin
  • Macrolides
  • Aminoglycosides
  • Lincosamides
  • Linezolid
  • Chloramphenicol
  • Tetracyclines
  • Streptogramins
35
Q

Bacterial ribosomes

A
  • 70S –> 30S + 50S subunits
  • Free in the cytoplasm
  • Bind to mRNA
  • Form polysomes (cluster of ribosomes held together by a strand of mRNA that each ribosome is translating)
  • Display receptors for antibiotics on either subunit
36
Q

Eukaryotic ribosomes structure and relevance to antibiotics

A

80S –> 40S + 60S subunits

Allows for antibiotics to be selective for bacterial ribosomes and not eukaryotic ribosomes; however, due to the simularities, ribosomal antibiotics have some degree of toxicitiy

37
Q

Bacterial protein synthesis main steps

A
  1. ) Initiation (binds mRNA)
  2. ) Aminoacyl-tRNA binding (delivers AA)
  3. ) Transpeptidation by peptidyl transferase (growing peptide and new AA combined)
  4. ) Translocation (ribsome slides over on mRNA to next codon)
38
Q

Which ribosomal antibiotics effect the 30S subunit?

What step of translation do they effect?

A
  • Spectinomycin
  • Aminoglycaosides
  • Tetracyclines

I SAT on the small subunit

39
Q

What ribosomal antibiotics effect the 50S subunit?

What step of translation do they each effect?

A

All of the ones that don’t effect the 30S

  • Chloramphenicol
  • Macrolides
  • Lincosamides
  • Streptogramins
  • Linezolid
40
Q

Spectinomycin

  • Structure
  • Bactericidal or Bacteriostatic?
  • Which subunit does it bind?
  • Mechanism of action?
A
  • Aminocyclitol that is structurallly related to aminoglycosides
  • Bacteriostatic
  • Binds 30S subunit
  • Inhibits formation of 70S initiation complex
41
Q

Mechanism of Spectinomycin resistance

A
  • Production of drug inactivating enzyme

- Alteration of specific receptor on 30S subunit

42
Q

Aminoglycosides examples

A
  • Neomycin
  • Gentamicin
  • Streptomycin
43
Q

Aminoglycosides mechanism of action

A
  • Binds to 30S subunit
  • Blocks formation of 70S initiation complex
  • Causes misreading of mRNA
  • Prevent polysome formation, resulting in nonfunctional monosome
  • Irreversibly inhibits protein synthesis –> bactericidal
44
Q

Aminoglycosides mechanisms of resistance

A
  • Produce (plasmid-mediated) drug-inactivating group transferases –> includes:
  • Aminoglycoside acetyltransferase
  • Aminoglycoside adenyltransferase
  • Aminoglycoside phosphotransferase
  • Alter 30S subunit (lowers affinity for Abx)
  • Alter permeability
45
Q

Tetracyclines mechanism of action

A
  • Bind 30S subunit
  • Inhibit binding of aminoacyl-tRNA to mRNA-ribosomal complex
  • Bacteriostatic
46
Q

Tetracycline mechanism of drug resistance

A
  • Efflux of drugs by plasmid-coded efflux protein pump (Unique to Tetracyclines!)
  • Altered permeability to drug
  • Enzymatic inactivation of the drug
47
Q

Chloramphenicol mechanism of action

A
  • Binds 50S subunit
  • Bacteriostatic
  • Inhibits Peptidyl Transferase (in transpeptidation)
48
Q

Chloramphenicol mechanism of drug resistance

A
  • Produce (plasmid-coded) drug inactivating enzyme: Chloramphenicol Acetyltransferase
  • Reduce permeability
49
Q

Macrolides example

A

Erythromycin

50
Q

Macrolides mechanism of action

A
  • Bind 50S subunit
  • Bacteriostatic
  • Prevent the ribosome from translocation down the mRNA
51
Q

Macrolides mechanism of drug resistance

A
  • Methlyation of the receptor on the 50S subunit (plasmid-coded methylase) results in decreased affinity for the Abx
  • Drug inactivating enzymes (esterases that hydrolyze macrolides)
  • Reduced permeability to the drug
52
Q

Lincosamides examples

A
  • Lincomycin

- Clindamycin

53
Q

Lincosamides mechanism of action

A
  • Binds 50S subunit
  • Prevent the ribosome from translocating down the mRNA
  • Bacteriostatic
54
Q

Lincosamide mechanism of drug resistance

A
  • Methlation of the ribosomal receptor site
  • Production of drug inactivating enzymes
  • Reduced permeability to the drug
55
Q

Streptogramins mechanism of action

A
  • Binds to different sites on 50S ribosomal subunit
  • Works syndergistically to prevent the ribosome from translocating down the mRNA
  • For most susceptible organisms, they are bactericidal
56
Q

Streptogramins mechanism of drug resistance

A
  • Methylation of the quinupristin (S-type B) binding site
  • Production of drug inactivating enzyme
  • Active transport efflux
57
Q

Streptogramins example

A

Synercid –> Composed of Streptogramins B & A (also known as quinupristin and dalfopristin)

58
Q

MLS-type B resistance

A
  • Macrolide-Lincosamide-Streptogramin-B resistance

- Methylase production confers resistance to the above antibiotics as they have the same ribosomal binding site

59
Q

Linezolid mechanism of action

A
  • Binds to unique site located on 23S rRNA of the 50S subunit
  • Inhibit the formation of 70S ribosome (initiation complex)
  • Also inhibits translocation of peptidyl-tRNA
60
Q

Linezolid mechanism of drug resistance

A
  • Mutation of the binding site on 23S rRNA (decreases affinity for Abx)
61
Q

Sulfonamides and Trimethoprim drug class

A

Antifolate drugs (often used in combination with eachother)

62
Q

Sulfonamides mechanism of action

A
  • As antimetabolites of PABA (para-aminobenzoid acid) they are competitive inhibitors of DHPS (dihydrop’teroate synthase) in bacteria (competing with the PABA precursor)
63
Q

Sulfonamides mechanism of resistance

A
  • Decrease intracellular accumulation
  • Increase in production of PABA
  • Decrease in sensitivity of DHPS to the drugs
64
Q

Trimethoprim mechanism of action

A

Act as a selective inhibitor of DHFR (dihydrofolate reductase)

65
Q

Trimethoprim mechanism of resistance

A

Decrease in the sensitivity of DHFR to the Abx

66
Q

Fluoroquinolones mechanism of action

A
  • Inhibit prokaryotic topisomerase II (DNA Gyrase) and topiosomerase IV
  • Bactericidal
67
Q

Fluoroquinolones mechanism of resistance

A
  • Decrease in intracellular accumulation (efflux pump or change in porin structure)
  • Chromsome-encoded mutation in DNA gryase
  • Plasmid-mediated resistance
68
Q

Penicillins, Cephalosporins, Monobactams, and Carbapenems general mechanism of action

A
  • Bind to PBPs as Ala-AAla analogs
  • Inhibit transpeptidase
  • Inhibit cross-linking of peptidoglycan polymers
  • Activate autolysins
69
Q

Penicillin, main mechanisms of resistance

A
  • B-lactamases

- Modification of PBPs (Ex. MRSA/E and PRSP)

Block 1 - Week 4 (11 decks)

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