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Drugs, Microbes, Host – The Elements of Chemotherapy. Chapter 13. History of Microbiology. Chemotherapy – treatment with chemicals 1910: Paul Ehrlich developed a synthetic arsenic drug, salvarsan, to treat syphilis.

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History of Microbiology

Chemotherapy – treatment with chemicals

  • 1910: Paul Ehrlich developed a synthetic arsenic drug, salvarsan, to treat syphilis.

  • 1922: Alexander Fleming discovered lysozyme in tears, saliva and sweat. Lysozyme was the first body secretion shown to have chemotherapeutic properties!

  • 1930s: Sulfonamides were synthesized

    and are still used!


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History of Microbiology

1928: Alexander Fleming discovered the first antibiotic.

  • He observed that Penicillium fungus made an antibiotic, penicillin, that killed S. aureus.

  • 1940s: Penicillin was tested clinically and mass produced.


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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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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.

Take advantage of any cellular/molecular differences between host (patient) and microbe!


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Targets of Antimicrobial Drugs

  • Inhibition of cell wall synthesis

  • Disruption of cell membrane structure or function

  • Inhibition of protein synthesis

  • Inhibition of nucleic acid synthesis, structure or function

  • Block metabolic reactions



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1. Drugs that Affect the Bacterial Cell Wall

Most bacterial cell walls contain a rigid girdle of peptidoglycan.

Penicillin and cephalosporin block synthesis of peptidoglycan, causing the cell wall to lyse.

Penicillins do not penetrate the outer membrane and are less effective against gram-negative bacteria.

Broad spectrum penicillins and cephalosporins can cross the outer membranes of gram-negative bacteria.


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Penicillins

Large diverse group of compounds

Can synthesized in the laboratory

More economical to obtain natural penicillin through

microbial fermentation and modify it to semi-synthetic forms

Penicilliumchrysogenum – major source

All penicillins consist of 3 parts

thiazolidine ring

beta-lactam ring

variable side chain dictates microbial activity


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Chemical Structure of Penicillins

The R group is responsible for the activity of the drug, and cleavage of the beta-lactam ring will render the drug inactive.

Penicillinase (β-lactamase)


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Semisynthetic Penicillins

  • Penicilinase-resistant penicillins

    • Carbapenems: very broad spectrum

    • Monobactam: Gram negative

  • Extended-spectrum penicillins

  • Penicillins + -lactamase inhibitors

    • Primary problems – allergies and resistant strains of bacteria


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    Cephalosporins

    Account for majority of all antibiotics administered

    Isolated from Cephalosporium acremonium mold

    Beta-lactam ring that can be altered

    Relatively broad-spectrum, resistant to most penicillinases, & cause fewer allergic reactions

    • 2nd, 3rd, and 4th generations more effective against gram-negatives



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    Other Inhibitors of Cell Wall Synthesis

    • Bacitracin

      • Topical application

      • Against gram-positives

    • Vancomycin

      • Glycopeptide

      • Important "last line" against antibiotic resistant S. aureus


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    2. Drugs That Disrupt Cell Membrane Function

    A cell with a damaged membrane dies from a 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

    • Polymyxin B (Gram negatives)

      • Topical

      • Combined with bacitracin

        and neomycin (broad spectrum)

        in over-the-counter preparation


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    Targets of Antimicrobial Drugs

    • Inhibition of cell wall synthesis

    • Disruption of cell membrane structure or function

    • Inhibition of protein synthesis

    • Inhibition of nucleic acid synthesis, structure or function

    • Block metabolic reactions


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    Ribosomes of eukaryotes differ in size and structure from prokaryotes, so antimicrobics usually have a selective action against prokaryotes. But they can also damage the eukaryotic mitochondria.

    Streptomycin inserts on sites on the 30S subunit and cause misreading of mRNA.

    Tetracyclines block attachment of tRNA on the A acceptor site and stop further synthesis.

    50S

    30S

    3. Drugs That Block Protein Synthesis


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    Protein Synthesis Inhibitors prokaryotes, so antimicrobics usually have a selective action against prokaryotes. But they can also damage the eukaryotic mitochondria.

    Tetracycline Antibiotics

    • Broad-spectrum, block protein synthesis (blocks attachment of tRNA)

    • Low cost

    • Doxycycline & minocycline – oral drugs taken for STDs, Rocky Mountain spotted fever, Lyme disease, typhus, acne & protozoa


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    3. Drugs That Block Protein Synthesis prokaryotes, so antimicrobics usually have a selective action against prokaryotes. But they can also damage the eukaryotic mitochondria.

    streptomycin

    30S

    30S

    = know these


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    Protein Synthesis Inhibitors prokaryotes, so antimicrobics usually have a selective action against prokaryotes. But they can also damage the eukaryotic mitochondria.

    Chloramphenicol

    • Isolated from Streptomyces venezuelae

    • Potent broad-spectrum drug with unique nitrobenzene structure

    • Blocks peptide bond formation

    • No longer derived from natural source

    • Very toxic, restricted uses, can cause irreversible damage to bone marrow

    • Typhoid fever, brain abscesses, rickettsial & chlamydial infections


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    Protein Synthesis Inhibitors prokaryotes, so antimicrobics usually have a selective action against prokaryotes. But they can also damage the eukaryotic mitochondria.

    Erythromycin

    • Also inhibits protein synthesis (attaches to bacterial ribosomes)

    • Broad-spectrum, (side effects: fairly low toxicity!)

      • Given to children

    • Taken orally for Mycoplasma pneumonia, legionellosis, Chlamydia, pertussis, diptheria and as a prophylactic prior to intestinal surgery

    • Newer semi-synthetic macrolides – clarithomycin, azithromycin


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    Know this!!! prokaryotes, so antimicrobics usually have a selective action against prokaryotes. But they can also damage the eukaryotic mitochondria.


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    4. Inhibitors of Nucleic Acid Synthesis prokaryotes, so antimicrobics usually have a selective action against prokaryotes. But they can also damage the eukaryotic mitochondria.

    • Rifamycins (Rifampin)

      • Inhibits RNA synthesis (transcription!)

      • Leprosy, Tuberculosis,

    • Quinolones

      • Ciprofloxacin (cipro)

      • Inhibits DNA gyrase

      • Wide applications (including…respiratory and urinary tract infections, anthrax)


    Targets of antimicrobial drugs27 l.jpg
    Targets of Antimicrobial Drugs prokaryotes, so antimicrobics usually have a selective action against prokaryotes. But they can also damage the eukaryotic mitochondria.

    • Inhibition of cell wall synthesis

    • Disruption of cell membrane structure or function

    • Inhibition of protein synthesis

    • Inhibition of nucleic acid synthesis, structure or function

    • Block metabolic reactions


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    5. Drugs That Block Metabolic Reactions prokaryotes, so antimicrobics usually have a selective action against prokaryotes. But they can also damage the eukaryotic mitochondria.

    • Sulfonamides and trimethoprim block enzymes required for tetrahydrofolate synthesis needed for DNA & RNA synthesis. Broad spectrum!

    • Competitive inhibition – drug competes with normal substrate for enzyme’s active site

    • Synergistic effect – an additive effect, achieved by multiple drugs working together, requiring a lower dose of each


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    New Classes of Antibiotics prokaryotes, so antimicrobics usually have a selective action against prokaryotes. But they can also damage the eukaryotic mitochondria.

    • 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


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    Miscellaneous Antibacterial Drugs prokaryotes, so antimicrobics usually have a selective action against prokaryotes. But they can also damage the eukaryotic mitochondria.

    • Isoniazid – used with rifampicin to treat TB (primary treatment)

      • Inhibits mycolic acid synthesis in the mycobacterial cell wall

    • Oxazolidinones-new class of antibacterial drugs inhibit initiation of protein synthesis

      • Linezolid – MRSA (Methicillin-Resistant Staphylococcus aureus)

        VRE (Vancomycin-Resistant Enterococcus)

    • Fluoroquinolones –broad-spectrum, potent

      • norfloxacin, ciprofloxacin (cipro) – UTI, STD, GI, osteomyletitis, respiratory & soft tissue infections

      • sparofloxacin, levofloxacin – pneumonia, bronchitis, sinusitis


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    Fungi of Medical Importance prokaryotes, so antimicrobics usually have a selective action against prokaryotes. But they can also damage the eukaryotic mitochondria.

    • Fungal diseases are referred to as mycoses

    • Cutaneous mycoses (dermatophytoses)

      • Fungi have keratinase – degrade keratin on skin, nails and hair

    • Examples: ringworm, athletes foot, jock itch

    • Systemic mycoses

      • Usually caused by soil fungi

      • Special problems in immunocompromised hosts

      • Examples: pneumocystis pneumonia, valley fever


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    Disrupt prokaryotes, so antimicrobics usually have a selective action against prokaryotes. But they can also damage the eukaryotic mitochondria.

    plasma

    membrane

    Antifungal Drugs

    • Amphotericin B–mimic lipids, most versatile & effective, topical & systemic treatments

    • Nystatin – topical treatment

  • Griseofulvin – stubborn cases of dermatophyte infections (jock itch, athlete’s foot)

  • Flucytosine – analog of cytosine; cutaneous mycoses or in combination with amphotericin B for systemic mycoses


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    Antiparasitic Drugs prokaryotes, so antimicrobics usually have a selective action against prokaryotes. But they can also damage the eukaryotic mitochondria.

    • Antimalarial drugs –

      • Quinine, chloroquinine, primaquine,

    • Antiprotozoan drugs –

      • Metronidazole (Flagyl), quinicrine, sulfonamides, tetracyclines

    • Antihelminthic drugs – immobilize, disintegrate, or inhibit metabolism

      • Mebendazole -- broad-spectrum:

        • inhibit function of microtubules, interfers with glucose utilization & disables them

      • pyrantel, piperazine- paralyze muscles

      • niclosamide – destroys scolex


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