Drugs, Microbes, Host The Elements of Chemotherapy

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Drugs, Microbes, Host The Elements of
Chemotherapy
Chapter 12
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How you should approach this chapter

• Antimicrobial chemotherapy and antimicrobics
• What are selection criteria?
• How are they used?
• What are adverse effects?
• HOW DO THEY WORK (what is their mode of action)?
• Blocks or inhibits
• Cell wall synthesis
• nucleic acid structure/function
• protein synthesis
• cell membrane structure/function
• (Specific metabolic pathways)

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• Antibacterial drugs Antibiotics and Synthetics
  (what is the difference?)
• Classes/categories know source, mode of action,
  application/spectrum
• Antibiotics penicillins, cephalosporins, other
  B-lactam Abt, aminoglycosides, tetracyclines and
  other Streptomyces antibiotics, Bacillus
  antibiotics, other new drugs
• Synthetics sulfonamides, flouroquinolones,
  others (narrow and broad spectrum)

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• Other antimicrobials antifungals, antiprotozoal,
  anthelminthics, antiviral.
• Drug resistance How? Why? Effect?
• Side effects of drugs toxicity, allergy,
  superinfection
• Skim pp. 375-379

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Origins of antimicrobial drugs

• Antibiotics are common metabolic products of
  aerobic spore-forming bacteria fungi.
• bacteria in genera Streptomyces Bacillus
• molds in genera Penicillium Cephalosporium
• By inhibiting the other microbes in the same
  habitat, antibiotic producers have less
  competition for nutrients space.

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Selectively toxic

• Drugs should kill or inhibit microbial cells
  without simultaneously damaging host tissues.
• As the characteristics of the infectious agent
  become more similar to the vertebrate host cell,
  complete selective toxicity becomes more
  difficult to achieve more side effects are seen.

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Targets of antimicrobial drugs

• Inhibition of ____________________
• Inhibition of ____________________
  ____________________
• Inhibition of ____________________
• Disruption of ____________________
  ____________________

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1. Drugs that affect the bacterial cell wall

• Penicillin and cephalosporin block synthesis of
  peptidoglycan, causing the cell wall to lyse.
• Other drugs include vancomycin, bacitracin,
  monobactams, fosfomycin, cycloserine

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2. Drugs that inhibit nucleic acid synthesis

• may block synthesis of nucleotides, inhibit
  replication, or stop transcription
• ____________________ drug competes with normal
  substrate for enzymes active site
• ____________________ an additive effect,
  achieved by multiple drugs working together,
  requiring a lower dose of each

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2. Drugs that inhibit nucleic acid synthesis

• Sulfonamides and trimethoprim (synergistic) --
  block enzymes required for tetrahydrofolate
  (THFA) synthesis
• THFA is needed for DNA RNA synthesis.
  (coenzyme)
• Quinolones (ciprofloxacin) blocks gyrase
• Rifampin blocks RNA pol (transcription)

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3. Drugs that block protein synthesis

• Ribosomes of eucaryotes differ in size and
  structure from procaryotes, so antimicrobics
  usually have a selective action against
  procaryotes. But they can also damage the
  eucaryotic mitochondria.
• Abt can block mRNA, peptide bonds, tRNA binding,
  etc.

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4.Drugs that disrupt cell membrane function

• A cell with a damaged membrane dies from
  disruption in metabolism or lysis.
• These drugs have specificity for a particular
  microbial group, based on differences in types of
  lipids in their cell membranes.
• Polymyxins interact with phospholipids and cause
  leakage, particularly in gram-negative bacteria
• Amphotericin B and nystatin form complexes with
  sterols on fungal membranes which causes leakage.

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4. Drugs that disrupt cell membrane function
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Survey of major antimicrobial drug groups

• Antibacterial drugs
• Antibiotics
• Synthetic drugs
• Antifungal drugs
• Antiparasitic drugs
• Antiviral drugs
• About 260 different antimicrobial drugs are
  classified in 20 drug families.

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Antibacterial antibiotics

• Penicillins
• Cephalosporins
• Other beta-lactam antibiotics
• Aminoglycosides
• Tetracycline antibiotics
• Chloramphenicol
• Other Streptomyces antibiotics
• The Bacillus antibiotics
• New classes

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Penicillins

• Source Penicillium
• Examples -cillin such as penicillin,
  ampicillin, amoxicillin, methicillin etc.
• MOA blocks PGN synthesis (CW)
• Application Gram positive, some Gram neg.
• Structure B-lactam, thiaxolidine, varying side
  chains
• Problems allergy, bleeding, diarrhea(host)
  resistance in bacteria (via lactamase,
  penicillinase)

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Penicillins
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Cephalosporins

• Source Cephalosporium
• Examples Ceph- cef- kef- drugs (ex. Cephalexin)
• MOA blocks CW synthesis
• Application depends on generation
• Structure B-lactam, ring, varying side chains
  (2)
• Problems less allergies, but some need
  parenteral administration, can affect WBC

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Cephalosporins - generations
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Other beta-lactam antibiotics

• Imipenem broad-spectrum drug for infections
  with aerobic and anaerobic pathogens
• Aztreonam isolated from bacteria Chromobacterium
  violaceum newer narrow-spectrum drug for
  infections by gram-negative aerobic bacilli. May
  be used by people allergic to penicillin- it is a
  monobactam.

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MOA of B-lactam antibiotics

• PGN (made of NAM and NAG) are cross-linked by the
  enzyme transpeptidase
• This is the final step in CW syntheis
• B-lactam abt inhibit transpeptidase they mimic
  the normal substrate and bind to the active site.

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aminoglycosides

• Source Actinomycetes (like Streptomyces)
• Examples streptomycin, gentamicin, amikacin,
  neomycin
• MOA blocks translation (inhibits initation,
  binds 30S ribosomal subunit)
• Application relatively broad
• Structure 6C ring with 2 amino sugars
• Problems diarrhea, kidney, EAR problems

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Aminoglycosides
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Other antibiotics produced by StreptomycesA.
Tetracyclines
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tetracyclines

• MOA block protein synthesis (30S)
• Application Broad-spectrum, Doxycycline
  minocycline oral drugs taken for STDs, Rocky
  Mountain spotted fever, Lyme disease, typhus,
  acne protozoa
• Problems kills GI flora, can discolor teeth in
  children, causes photosensitization

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B. Chloramphenicol

• Source Streptomyces venezuelae is totally
  synthetic now
• MOA Blocks peptide bond formation
• Application Potent broad-spectrum drug with
  unique. Typhoid fever, brain abscesses,
  rickettsial chlamydial infections
• Structure nitrobenzene
• Problems Very toxic, restricted uses, can
  cause irreversible damage to bone marrow

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C. Erythromycin

• MOA Attaches to ribosome (50S)
• Application
• Broad-spectrum, fairly low toxicity.
• Taken orally for Mycoplasma pneumonia,
  legionellosis, Chlamydia, pertussis, diptheria
  and as a prophylactic prior to intestinal surgery
• For penicillin-resistant gonococci, syphilis,
  acne
• Newer semi-synthetic macrolides clarithomycin,
  azithromycin
• Structure macrolide, large lactone ring with
  sugars

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Macrolide antibiotic
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Other Streptomyces antibiotics

• Clindamycin broad-spectrum, serious abdominal
  anaerobic infections
• Vancomycin narrow-spectrum, effective against
  penicillin methicillin resistant staphylococcal
  infections very toxic, hard to administer
  inhibits CW synthesis (NAM/NAG polymerization)
• Rifampin limited spectrum, cannot pass through
  many cell membranes, used to treat gram-positive
  bacteria, TB, leprosy
• Blocks TRANSCRIPTION

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The Bacillus antibiotics

• Bacitracin-
• MOA Blocks CW synthesis
• Application narrow-spectrum, major ingredient of
  neosporin ointment
• Polymyxin
• MOA peptide with fatty acid component, detergent
  activity
• Application narrow-spectrum drug resistant
  Pseudomonas aeruginosa UTI
• Problems limited by toxicity to kidney

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New classes of antibiotics

• Fosfomycin trimethamine a phosporic acid
  effective as alternate treatment for UTIs,
  inhibits cell wall synthesis
• Synercid effective against Staphylococcus
  Enterococcus that cause endocarditis surgical
  infections inhibits protein synthesis (binds
  50S)

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II. Synthetic antibacterial drugs

• Sulfonamides, sulfa drugs first antimicrobic
  drugs
• Sulfisoxazole shigellosis, UTI, protozoan
  infections
• Silver sulfadiazine burns, eye infections
• Trimethoprim given in combination with
  sulfamethoxazole UTI, PCP
• Sulfonamides and trimethoprim block THFA synthesis

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A. Sulfonamides
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B. Miscellaneous antibacterial drugs

• Isoniazid used with rifampin to treat TB blocks
  FA reductase (metabolism)
• Oxazolidinones- new class of antibacterial drugs
  inhibit initiation of protein synthesis
• Linezolid MRSA, VRE
• Fluoroquinolones broad-spectrum, potent block
  prokaryotic gyrase
• norfloxacin, ciprofloxacin UTI, STD, GI,
  osteomyletitis, respiratory soft tissue
  infections
• sparofloxacin, levofloxacin pneumonia,
  bronchitis, sinusitis