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Drugs, Microbes, Host The Elements of Chemotherapy

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How you should approach this chapter... Antimicrobial chemotherapy and antimicrobics ... Mycoplasma pneumonia, legionellosis, Chlamydia, pertussis, diptheria and as a ... – PowerPoint PPT presentation

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Title: Drugs, Microbes, Host The Elements of Chemotherapy


1
Drugs, Microbes, Host The Elements of
Chemotherapy
Chapter 12
2
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)

3
continued
  • 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)

4
continued
  • 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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7
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.

8
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.

9
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

14
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.

19
4. Drugs that disrupt cell membrane function
20
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.

21
Antibacterial antibiotics
  • Penicillins
  • Cephalosporins
  • Other beta-lactam antibiotics
  • Aminoglycosides
  • Tetracycline antibiotics
  • Chloramphenicol
  • Other Streptomyces antibiotics
  • The Bacillus antibiotics
  • New classes

22
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)

23
Penicillins
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25
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

26
Cephalosporins - generations
27
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.

28
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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30
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

31
Aminoglycosides
32
Other antibiotics produced by StreptomycesA.
Tetracyclines
33
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

34
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

35
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

36
Macrolide antibiotic
37
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

38
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

39
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)

40
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

41
A. Sulfonamides
42
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
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