Antibiotics

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Antibiotics Waksman compounds produced by
one organism which inhibits the growth of or
kills other organisms. natural compounds vs.
synthetic
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Antibiotics antibiotic action cidal
bactericidal, fungicidal, virucidal kill
the pathogen stasis bacteriostatic,
fungistatic prevent cell growth and
division, but do not kill
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Antibiotics

• Selective toxicity, attack unique functions of
  infective agents
• ______________ Therapeutic index
• Therapeutic dose
• Want Therapeutic index to be large

Toxic dose
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Selective targets for antibiotics Cell wall
synthesis Protein synthesis Nucleic
acid synthesis Metabolism blockers
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Characteristics

• Spectrum of activity (narrow or broad)
• Effect on target (cidal versus static)
• Route of administration
• Target susceptibility
• Attainable concentration in body
• Effective concentration
• Minimum inhibitory concentration (MIC)
• Minimum lethal concentration
• MLC2-4x MIC for cidal drugs

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Sulfa Drugs (Sulfonamides)

• Structural analogs of p-aminobenzoic acid
• PABA is cofactor for synthesis of Folic acid
• Folate is used in synthesis of purines and
  pyrimidines
• Effective against bacteria that do not take up
  folate, and normally synthesize it

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Quinolones

• Inhibit DNA gyrase (topoisomerase II)
• Gyrase induces negative DNA supercoiling, relaxes
  torsional strain on DNA
• Gyrase is required for transcription,
  replication, repair

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Penicillins

• Feature ß-lactam ring
• Possible mechanisms of action
• Inhibit transpeptidation in peptidoglycan
• Activate of autolytic enzymes
• Stimulate holins to form membrane lesions
• Limitations
• Allergic reactions, destruction by stomach
  acids, cleavage by ß-lactamases

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Cephalosporins

• ß-lactam structure similar to penicillins
• Also inhibit transpeptidation reactions
• Can be given to those with penicillin allergies

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Tetracyclines

• Four rings
• Combine with 30S small ribosomal subunit to block
  entry of tRNA into A site
• Broad spectrum activity

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Aminoglycosides

• Streptomycin, neomycin, kanamycin, gentamicin,
  tobramycin
• Bind to small ribosomal subunit to block
  translation initiation and/or cause misreading

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Macrolides

• Erythromycin, contain 12-22 C lactone ring
• Bind 23S rRNA of large (50S) subunit to block
  chain elongation
• Bacteriostatic

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Chloramphenicol

• Binds 23S rRNA on 50S subunit
• Inhibits peptidyl transferase activity
• Bacteriostatic
• Broad spectrum, but highly toxic

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Drug Resistance Mechanisms

• Block drug binding or uptake
• Multidrug resistance pumps
• Related to chemotherapy-resistance pumps in
  humans
• Export structurally unrelated drugs
• Drug inactivation (ß-lactamase)
• Target function mutation
• Use of alternate biochemical pathway

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Drug Resistance

• R plasmids may transmit several genes
• Overuse of antibiotics promotes spread

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Drug Resistance

• Control, reduce, cycle antibiotic use
• Improve hygiene in hospitals reduce patient
  movement
• Develop/discover new antibiotics
• Modify existing antibiotics
• Develop inhibitors of modifying enzymes
• Develop cures for resistance plasmids

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Combating Drug Resistance

• New procedures to combat

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Antifungals

• Interfere with membrane sterols
• Nystatin, amphotericin B
• Block chitin synthase
• Polyoxin D, nikkomycin

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Prophylactic use of antibiotics
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Toxicity mild reactions allegic reactions
to anaphylaxis anaphylactic shock toxic
effects blood dyscrasia (chloramphenicol) hemol
ytic anemia (sulfonamides) blood platelet
activity depression (many) liver damage
(several) kidney damage ( aminoglycosides)
normal flora depression diarrhea pseudomembranou
s colitis (C. difficile) yeast infections
mouth, vagina, intestinal tract