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103 Cards in this Set
- Front
- Back
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Examples: Beta-lactams
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Penicillins (can combine with aminoglycosides in fermenting bacteria)
Cephalosporins Carbapenems Monolactams |
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Structure: Beta-lactams
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beta-lactam 3 carbon cyclic amide
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Target: Beta-lactams
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Cell wall synthesis: Penicillin binding proteins
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Mechanism: Beta-lactams
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BLOCK TRANSPEPTIDATION
Mimic D-Ala-D-Ala dipeptide Form Covalente Adduct on Serine in penicillin binding protein binding site |
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Resistance: Beta-lactams
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beta-lactamases cleave lactam ring (can inhibit with beta-lactamase inhibitor)
carrbapenemases mutation in PBP gene-->decrease drug affinity alter intake into gram - outer membrane porins or efflux pump |
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Examples: Glycopeptides (Cell Wall)
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Vancomycin
Teichoplanin |
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Structure: Glycopeptides
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Seven aa peptide. Needs oxidation and glycosylation to complete synthesis
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Target: Glycopeptides
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D-Ala-D-Ala dipeptide
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Mechanism: Glycopeptides
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Binds D-Ala-D-Ala terminus of newly linked peptidoglycan (post transglyco, pre transpep)
--> Inhibits wall SYNTHESIS |
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Resistance: Glycopeptides
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Non-protein cell wall component target (no mutational resistance)
(1)change in cell wall composition: D-Ala-D-Ala D-Ala-D-Lac (make precursors, link it on) --> loss of recognition (Vancomycin Resistant Enterococci – VRE) |
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Source: Glycopeptides
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Bacteria. Synthesized by Non-Ribosomal-Peptide-Synthase (NRPS), w/out ribosome
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Combinations: Glycopeptides
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Do: combine with beta-lactams (common pathway)
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Structure: Bacitracin (Cell Wall)
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Thiazalone ring
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Target: Bacitracin
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topical against Gram + organisms
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Mechanism: Bacitracin
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Binds to lipid carrier, inhibits LIPID DEPHOSPHORYLATION
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Source: Bacitracin
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Soil bacteria via NRPS
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Target: Cycloserine
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"second line" anti-TB
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Mechanism: Cycloserine
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Competitive agonist of Alanine racemase and D-Alanine ligase
--> Inhibits wall SYNTHESIS |
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Source: Cycloserine
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bacteria
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Structure: Phosphonomycin
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epoxide ring
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Target: Phosphonomycin
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UTIs
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Mechanism: Phosphonomycin
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Reacts with cysteins thiol in active site of Enolpyuruvate tranferase, Blocks NAG-->NAM CONVERSION
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Source: Phosphonomycin
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Bacteria
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Examples: Mycolic Acid Synthesis Inhibitors
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Isoniazid
Ethambutol Ethionamide |
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Target/Mechanism: Mycolic Acid Synthesis Inhibitors
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Inhibit mycolic acid synthesis, an integral cell wall component of mycobacterium TB
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Target: Lipopeptides (Membrane)
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cell membrane of GRAM + ONLY
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Mechanism: Lipopeptides
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Attach to cell membrane of gram + (IN PRESENCE OF Ca++), form pore-->DEPOLARIZATION -->death/lysis
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Resistance: Lipopeptides
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mutations affecting overall membrane charge
(altered uptake not relevant b/c target is extracellular) |
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Source: Lipopeptides
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bactera
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Examples: Aminoglycosides (translation inhibitor)
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--mycins (from streptomyces) ex) streptomycin & tobramycin
--micins (from micromonospora) ex) gentamicin |
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Structure: Aminoglycosides
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ring with NH2 groups linked with glycosidic bonds
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Target: Aminoglycosides
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binds with 16S rRNA of 30S Ribosomal subunit at A-site
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Mechanism: Aminoglycosides
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binds 16S rRNA at A-site (different sequence than eukaryotes)
-->misread codons -->decrease efficiency of A--->P transition of nascent peptide -->bactericidal |
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Resistance: Aminoglycosides
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(1) Ezymatic inactivation Transferases: AAC (acetyl), ANT (Adenyl) and APH (phosphor) catalyze transfer of group onto side chain groups
(2) Altered Target Mutations in 16S rRNA molecule/rpsL gene (3) decrease net negative charge of membrane Fermenting bac don’t import. Efflux by MeXY pump (pseudomonas) |
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Source: Aminoglycosides
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bacteria (streptomyces/micromonospora)
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Example: Tetracyclines (inhibit translation)
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doxycycline
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What is special about glycyclines of tetracycline family?
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improved stability & binding affinity-->can overcome Ribosomal Protection Proteins
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Structure: Tetracyclines
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Naphthacene core modified to increase stability
lipophilic-->can diffuse through membrane |
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Target: Tetracyclines
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30S Ribosomal subunit
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Mechanism: Tetracyclines
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-->Reversible interaction with 30S subunit, block association of aa-tRNA to A-site
--> Also bind 70S subunit in mitochondria for ANTI-PARASITIC effect -->Bacteriostatic |
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Resistance: Tetracyclines
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(1) Inactivation: tetX gene (Bacteriodes) encode NADPH-dependant tetracycline oxioreductase
(2) Altered Target: RPP (Ribosomal Protection Proteins) – GTPase, related to EFs. Bind and induce conformational change to dislodge tetracycline (prevented by glycyclines) (3) Altered Uptake: Efflux pumps |
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Structure: Chloramphenicol (translation inhibitor)
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nitrated benzene attached to chlorinated hydroxypropamine
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Target: Chloramphenicol
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50S Ribosomal Subunit, interacts with 23S rRNA
--> Aplastic anemia side effect (not common in US) |
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Mechanism: Chloramphenicol
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-->Binds two specific adenine residues on 23S rRNA
-->Inhibits transpeptidation -->Bacteriostatic (mostly), bacteriocidal (for some) |
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Resistance: Chloramphenicol
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(1) Inactivation: Chloramphenicol AcetylTransferase (transferase), acetylates hydroxyl groups
(2) Altered Target: Rare mutations in 23S rRNA; Enxymatic methylation of key adenine NTs (3) Altered Uptake: gram- Porin mutations affect ease of entry, exportation by efflux |
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Source: Chloramphenicol
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isolated from bacteria, now synthesized
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Examples: Macrolides & Ketolides (translation inhibition)
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Erythromycin
Azythromycin (semi-synthetic) Clarithromycin (semi-synthetic) |
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Target: Macrolides & Ketolides
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interact with 23S rRNA of 50S ribosomal subunit
ketolide can overcome MLSB phenotype |
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Mechanism: Macrolides & Ketolides
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-->bind 23s rRNA of 50S near peptidyl transfer site
-->blocks nascent peptide from exit tunnel = dissociation of peptidyl-acyl tRNA -->Interfere with formation of 50S subunit -->Bacteriostatic (low conc), lethal at higher |
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Resistance: Macrolides & Ketolides
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(1) Inactivation: Phosphotraferases (mph A,B,C genes) or plasmid-encoded esterases (hydrolysis of lactone ring)
(2)Altered Target: Key site mutations in 23S rRNA, Methylases that target key adenine NTs (MLSB) |
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Source: Macrolides & Ketolides
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Macrolides: bacteria or synthetic derivation
Ketolides: semisynthetic erythromycin derivatives |
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Examples: Lincosamides (translation inhibitor)
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Lincomycin
Clindamycin (chlorinated) |
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Target: Lincosamides
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50S ribosomal subunit
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Mechanism: Lincosamides
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bind 23S rRNA near peptidyl transfer site (same as macrolides)
mechanism same as macrolides - block dissociation of peptidyl-acyl tRNA interfere with formation of 50S subunit |
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Resistance: Lincosamides
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Staph strains have enzyme that can nucleotidylate hydroxyl group
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Source: Lincosamides
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bacteria (streptomyces)
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Combinations: Lincosamides
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Don’t: combine erythromycin (macrolide erm-inducer) with clindamycin (erm positive but not constitutively)-->MLSB phenotype
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Structure: Streptogramins (translation inhibitor)
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SgA and SgB
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Target: Streptogramins
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50S Ribosomal Subunit (2 components bind in close proximity to different sites on 23S rRNA)
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Mechanism: Streptogramins
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-->A binds near the peptidyltranferase domain: Inhibits (transpeptidation - like chloramphenicol)
-->B-component interferes w/ exiting peptide (like macrolide) – dissociation -->Synergistic binding effect, irreversible, bactericidal |
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Resistance: Streptogramins
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(1) Inactivation: Vgb lyase, attacks C-O bond in B ring
(2) Altered target: methylation of Key adenine reduces affinity (MLSb Phenotype) (3) Altered Uptake: gram+ express efflux pumps, export linconsamides and streptogramin A MsrABC family members efflux macrolides and SgB |
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Source: Streptogramins
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Bacteria (streptomyces) via NRPS
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Example: Oxazolidinones (translation inhibitor)
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Linezolid
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Target: Oxazolidinones
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50S ribosomal subunit
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Mechanism: Oxazolidinones
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Bind at interface with 30S subunit, prevent formation of Pro 70S ribosome-->bacteriostatic
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Resistance: Oxazolidinones
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Altered target: Only known is 23S rRNA mutation, or staph Cfr methyltransferase
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Source: Oxazolidinones
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organically synthesized
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Examples: Fusidanes (translation inhibitor)
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Fusidic Acid
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Structure: Fusidanes
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steroid-like, similar to cephalosporin
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Mechanism: Fusidanes
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Binds ribosomal bound EF-G::GDP post hydrolysis, prevents dissociation and blocks elongation (no transition of de-aa-ed tRNA from P to E site)
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Resistance: Fusidanes
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(2) Altered target: mutations in fusA (encodes EF-G), decrease affinity
(3) Altered Uptake: Mutations, decrease permeability of membranes (4) UNKNOWN mechanism: FusB gene in PLASMID, cytosolic protein confers resistance |
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Source: Fusidanes
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fungi (Fusidium coccineum)
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Examples: Quinolones (Nucleic Acid Synthesis Inhibitor)
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Nalidixic acid
Fluroquinolone |
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Structure: Quinolones
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dual ring
fluroquinolones have F ion which drastically improves potency |
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Target: Quinolones
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Type II topoisomerases (gyrase & topoisomerase IV)
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Mechanism: Quinolones
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Bind DNA-Topoisomerase Complex, block ligation of double strand breaks
-->induce DNA-damage response: triggers bacteriophage lysis and toxin release (cholera and shiga) |
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Resistance: Quinolones
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(1) Inactivation: plasmid qnr gene protects (no clinical resistance, but allows mutation and resistance); altered AAC enzyme can acetylate-->low level resistance facilitates mutation development
(2) Altered target :mutations in gyrase (gram-) and topoisomerase IV (gram+), only mutations in one of two loci is required (3) Altered Uptake: Efflux pumps (MexAB & AcrAB), also plasmid encoded pumps rarely |
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Source: Quinolones
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Nalidixic acid is byproduct of chloroquine production
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Structure: Rifamycins (Transription inhibitor)
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Ansa structure
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Target: Rifamycin
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beta subunit of RNA polymerase (RpoB) deep within DNA:RNA channel
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Structure: Rifamycins (Transription inhibitor)
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Ansa structure
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Structure: Rifamycins (Transription inhibitor)
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Ansa structure
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Target: Rifamycin
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beta subunit of RNA polymerase (RpoB) deep within DNA:RNA channel
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Mechanism: Rifamycin
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Steric blockage of elongation-->abort transcription
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Structure: Rifamycins (Transription inhibitor)
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Ansa structure
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Structure: Rifamycins (Transription inhibitor)
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Ansa structure
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Resistance: Rifamycin
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Altered Target: Point mutations in the rpoB core region-->precludes binding+inhibition
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Mechanism: Rifamycin
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Steric blockage of elongation-->abort transcription
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Target: Rifamycin
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beta subunit of RNA polymerase (RpoB) deep within DNA:RNA channel
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Target: Rifamycin
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beta subunit of RNA polymerase (RpoB) deep within DNA:RNA channel
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Target: Rifamycin
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beta subunit of RNA polymerase (RpoB) deep within DNA:RNA channel
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Source: Rifamycin
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bacteria
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Mechanism: Rifamycin
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Steric blockage of elongation-->abort transcription
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Resistance: Rifamycin
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Altered Target: Point mutations in the rpoB core region-->precludes binding+inhibition
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Mechanism: Rifamycin
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Steric blockage of elongation-->abort transcription
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Mechanism: Rifamycin
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Steric blockage of elongation-->abort transcription
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Resistance: Rifamycin
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Altered Target: Point mutations in the rpoB core region-->precludes binding+inhibition
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Source: Rifamycin
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bacteria
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Resistance: Rifamycin
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Altered Target: Point mutations in the rpoB core region-->precludes binding+inhibition
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Source: Rifamycin
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bacteria
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Resistance: Rifamycin
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Altered Target: Point mutations in the rpoB core region-->precludes binding+inhibition
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Source: Rifamycin
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bacteria
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Source: Rifamycin
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bacteria
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