Antibiotics And Antibiotic Resistance (21)

Front 1

Peptidoglycan Synthesis:
3 Steps

Back 1

1.) synthesis of MurNAc-pentapeptide precursors (cytoplasm)
2.) lipid linkage and transport of disaccharide precursors across plasma membrane
3.) polymerization & crosslinking (extracellular)

Front 2

Vancomycin: Mechanism
(Glycopeptide)

Back 2

-bind Dala-Dala of peptide side chain in peptidoglycan precursors
-blocks PBPs from catalyzing transglycosylation/transpeptidation

Front 3

Vancomycin: General facts

Back 3

-glycosylated, cyclic non-ribosomally synthesized peptide antibiotic
-effective on many Gram +, not effective on Gram - (d/t permeability barrier/outer membrane, vancomycin in HUGE)
-used in cases of Beta lactam resistance (ex MRSA)

Front 4

Vancomycin Resistance

Back 4

Modification of antibiotic target
-bacteria produce altered petidoglycan structures that lack Dala-Dala (use Dala-Dlac)
-genes encoding resistance are usually found on plasmids or transposons
-often associated w enterococci in hospital settings (VRE: vancomycin resistant enterococci)
-VRStaphAureus emerged in 2001

Front 5

Cycloserine: Mechanism

Back 5

Inhibits peptidoglycan crosslinking
-mimics Dala and acts as competitive inhibitor in two sequential reactions: alanine racemase (alr) & Dala-Dala synthesase (ddl)
-if it outcompetes Dala and gets incorporated, no substrate for PBPs

Front 6

Bacitracin (neosporin): Mechanism

Back 6

-binds to pyrophosphate on the lipid carrier (bactoprenol-P) for PG precursors and blocks its recycling
-Group A Strep are 10x more sensitive, can be dx
-too toxic for systemic use

Front 7

Daptomycin: Mechanism

Back 7

-binds to and disrupts the cytoplasmic membrane
-novel mechanism, 2003, lipopeptide
-bactericidal, narrow spectrum (Gram +)

Front 8

Polymyxin: Mechanism

Back 8

-lipopetide, bactericidal, narrow spectrum (Gram -), high toxicity, novel mechanism
-binds LPS in outer membrane -> disrupts outer and cytoplasmic membrane

Front 9

Bacterial Ribosomes and Protein Synthesis

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30S + 50S (vs euks: 40S + 60S)
2 Phases of Synthesis:
-initiation: 30S + mRNA + tRNA
-elongation: + 50S

Front 10

Tetracycline: Mechanism

Back 10

-protein synthesis inhibitor (initiation)
-binds 30S, interferes w tRNA binding
-R groups alter pharmocology but not mechanism

Front 11

Tetracycline: General

Back 11

-bacteriostatic, broad spectrum
-side effects: stains teeth, upset stomach
-overuse -> resistance

Front 12

Tetracycline Resistance

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1) tetracycline efflux pump (most common)
2) mutations on the ribosome

Front 13

Aminoglycosides: Mechanism

Back 13

-protein synthesis inhibitor (initiation)
-binds irreversibly to 30S -> misreading and premature release of mRNA

Front 14

Aminoglycosides: General

Back 14

-gentamicin, amikacin, kanamycin, tobramycin
-bactericidal, broad spectrum, Gram -
-side effect: ototoxic, nephrotoxic

Front 15

Aminoglycoside Resistance

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-enzymatic modification of antibiotic to prevent it binding 30S
-transferases adenyl, acetyl, or phosphorylate aminoglycoside
-transferase genes found on plasmids and transposons

Front 16

Macrolides: Mechanism
(erythromycin, azithromycin, clarithromycin)

Back 16

-protein synthesis inhibitor (elongation)
-bind 50S to block elongation of proteins

Front 17

Macrolide Resistance

Back 17

1) efflux pumps
2) enzymatic modification (methylation) of ribosomal RNA (erm gene) = modification of antibiotic target

Front 18

Chloramphenicol: Mechanism

Back 18

-protein synthesis inhibitor (elongation)
-binds 50S to inhibit peptidyl transferase activity

Front 19

Chloramphenicol: General

Back 19

-bacteriostatic, toxicity (aplastic anemia), use in only severe infections
-toxicity d/t lack of specificity - inhibits ribosomes in mitochondria

Front 20

Chloramphenicol Resistance

Back 20

-bacterial chloramphenicol acetyltransferase catalyzes acetylation of chloramphenicol, prevents 50S binding (modification of antibiotic)

Front 21

Clindamycin: Mechanism

Back 21

-protein synthesis inhibitor (elongation)
-binds 50S to block protein elongation

Front 22

Clindamycin: General

Back 22

-bacteriostatic, ineffective against Gram - aerobes, useful in community acquired MRSA, tx for toxin-producing S. aureus

Front 23

Clindamycin Resistance

Back 23

-enzymatic modification (methylation) of rRNA (erm methylase gene) = modification of antibiotic target
-cross-resistance w macrolides d/t presence of erm gene

Front 24

Linezolid: Mechanism

Back 24

-protein synthesis inhibitor (early elongation)
-binds unique site on 50S, inhibits tRNA entry

Front 25

Linezolid: General

Back 25

-oxazolidinone class, 2000 (new), bacteriostatic
-tx of complicated S. aureus, Strep. pyogenes, Strep. agalactia
-not effective against most Gram -
-high cost

Front 26

Linezolid Resistance

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-point mutation in 50S prevents linezolid binding (modification of antibiotic target)
-no cross-resistance observed

Front 27

Fluoroquinolones: Mechanism

Back 27

-inhibit DNA replication
-bind bacterial DNA gyrase and topoisomerase -> inhibit DNA repair and replication

Front 28

Fluoroquinolones: General

Back 28

-bactericidal, broad spectrum
-side effects: tendon rupture, tendinitis

Front 29

Fluoroquinolones: Resistance

Back 29

-point mutations in bacterial DNA gyrase and topoisomerase (modification and antibiotic target)
-efflux pumps

Front 30

Metronidazole: General, Mechanism

Back 30

-anaerobic infections (C. difficile)
-in anaerobic environment -> radical production -> DNA damage

Front 31

Metabolic Analogs: Tetrahydrofolate

Back 31

-metabolic analogs act as competitive inhibitors to block normal biosynthetic pathways
-THF is required for bacterial growth: donates 1C groups for key molecules (nucleotides)
-sulfonamides & trimethoprim

Front 32

Indications for Use of Multiple Antibiotics

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1) prompt tx for undetermined pathogen in life-threatening infection
2) mixed infection by bacteria w different susceptibilities
3) avoid or delay emergence of resistant mutants during longs term therapy
4) synergy

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Synergy

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1) block metabolic pathway (sulfonamide & trimethoprim)
2) one drug enhances uptake of another
(penicillin enhances uptake of aminoglycosides)
3) one drugs prevents inactivation of another (clavulanic acid inactivates beta-lactamase)

Front 34

Biofilms

Back 34

-bacteria growing in multicellular aggregates on surface
- ++ polysaccharides
-responsible for many chronic infections

Front 35

Biofilms and Antibiotic Tolerance

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-exhibit enhanced tolerance (NOT genetically encoded)
-d/t "non growing" state
-Standard susceptibility measurements (MIC) do not account for biofilm tolerance

Front 36

Target cell wall biosynthesis

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-beta lactams
-vancomycin (glycoprotein)
-bacitracin
-cycloserine
-daptomycin
-polymyxin

Front 37

Target early stages of protein synthesis (initiation)

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-tetracycline
-aminoglycosides
-linezolid

Front 38

Target later stages of protein synthesis (elongation)

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-macrolides
-chloramphenicol
-clindamycin

Front 39

Target DNA repair and replication

Back 39

-fluoroquinolones

Front 40

Target DNA metabolism in anaerobic bacteria

Back 40

-metronidazole

Front 41

Antimetabolites

Back 41

-sulfonamides
-trimethoprim