Lecture #16: Chemotherapeutic Agents I Flashcards Preview

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Antibiotics are for Chemical Warfare

Produced by one soil organism to deter the growth of another. Competition for space in the soil.

Used to say they were produced by fungi. Now some of those fungi have been discovered to be bacteria that resemble fungi, Actinomycetes (High G + C). Blurred the nice distinction.

Effective against bacteria.


Antibiotics Source

Bacteria? Fungi? It’s both. Original drugs came from fungi. Penicillin and Streptomycin from Penicillium and Streptomyces (now a fungus-like bacterium). Common topical ointment from Bacillus.



a mixture of related cyclic polypeptides produced by organisms of the licheniformis group of Bacillus subtilis var Tracy, isolation of which was first reported in 1945.

As a toxic and difficult-to-use antibiotic, bacitracin does not work well orally. However, it is very effective topically, and is a common ingredient of eye and skin antibiotic preparations. Its action is on gram-positive cell walls.


Selective Toxicity

Either targets the bacterium or more strongly affects it vs. host.

At Best - AB only affects the target. Single out a unique process or structure.

Next best- Major effect on pathogen and minor effect on host.



Range of bacterial types affected.

Narrow Spectrum Drugs – one type (types can be whole groups). Gram +, Gram –, Mycobacterium.

Broad Spectrum Drugs – one type and some of another. Not ‘all bacteria.’ Gram + and some Gram -.


Nature of the Drugs We Use

Most are natural, just purified. Penicillin, Cephalosporin.

Some are natural form then modified to increase effectiveness (i.e., alter a side group). Semi-synthetic. Ampicillin, Methacillin.

Some are totally synthetic. Cipro(floxacin), Chloramphenicol.


Kirby-Bauer Assay System

Standard Method to Assess Drug Sensitivity. Basic way to test for sensitivity. Can be used to determine correct amount of drug to be administered against the strain of pathogen present.

Disk diffusion test. Freshly grown bacteria are used to inoculate the entire surface of a Mueller-Hinton agar plate. After the agar surface has dried for five minutes, the appropriate antibiotic disks are placed on it.

After 16-18 hours of incubation, the diameters of the zones of inhibition are measured to the nearest millimeter.


Competitive Inhibitors

Look-alikes for specific substrates. Enzyme will add in the drug instead of the correct substrate, make some ineffective compound or cell won’t get compound it needs.

Sulfa drugs inserted instead of correct substrate in the making of folic acid. Specific. Eucaryotes can’t make folic acid (lack enzymes) and must get it from their food. Bacteria make it. Unique process targeted.


Drugs That Target Cell Wall Biosynthesis

Penicillins, Ampicillin, and Cephalosporins. Most selective drugs.


Drugs That Target Protein Synthesis

Streptomycin, Erythromycin, Chloramphenicol, Tetracycline.


Drug That Targets Nucleic Acid Synthesis



Drug That Targets Cell Membranes

Polymixins (act like detergents). Least selective drug type.


Penicillium chrysogenum

‘Gold making’- makes color of the media gold.

The dark bands are sporangia, and this ascomycetous fungus is reproductive.

Common in the soil and rots fruits; oranges, melons. Although Fleming originally discovered its AB action in culture, a growth on a canteloup eventually led to a higher production alternative.


Cell Wall Biosynthesis

Penicillins and Cephalosporins. Have an active ring, β-lactam ring. Interferes with cross-linking of proteins in cell wall. Cells susceptible to lysis by osmotic change.

Microbes defend themselves from beta-lactam action with beta-lactamases. Build-up in a biofilm.

Inhibit transpeptidation enzymes involved in cross-linking the polysaccharide chains of the bacterial cell wall peptidoglycan. Activate cell wall lytic enzymes.



Prevent transpeptidation of peptidoglycan subunits by binding D-Ala-D-Ala amino acids at the end of peptide side chains. Thus it has a different binding site than that of the penicillins.



Blocks translation on the ribosome.
Prevents tRNA from attaching. Protein synthesis shuts down.

Bind to small ribosomal subunit (30S) and interfere with protein synthesis by directly inhibiting synthesis and causing misreading of mRNA.


Drugs that Affect NA Synthesis or Cell Membranes Not As Selective

Quinolones affect bacterial DNA Gyrase, so block replication and repair of chromosomes. Introduce negative twists in strands and thwarts proper DNA separation during cell division.

Polymixins act like detergents and break down membranes. Same in prokaryotes and eukaryotes, so only used topically (rub on skin rather than ingesting it).


Drugs Select for Resistant Individuals

Natural variation in a population. Slow but natural rate of mutation, bit faster in microbes than in eukaryotes. Variants arise.

Some may be resistant to a drug.


The Very Use of an Antibiotic is the First Step in Resistant Strains

Use AB only when needed, finish the full course prescribed, likely that you will wipe out the germ. If use them repeatedly, or do not finish full course, may open the door to the development of drug resistant types. You are selecting.


A Major Problem is Overkill

Parent or patient misinformation. AB’s ineffective against viruses. Demand for AB before can be sure it is a bacterial infection. Few days vs. over a week. May also just need to alleviate symptoms.

Powerful drugs from higher up in the arsenal when should try the standard ones first. Penicillin vs. Vancomycin or Kanamycin. Need to save some artillery!

Importance of finishing the course of treatment. Don’t want a residual weakened population to be able to spring back anew.


Drug Resistance

Resistant strains arise by mutation.


Drug use selects for the mutants that, by chance, acquired resistance.


Natural Drug Resistance

Outer coverings. Gram – organisms resist many drugs due to outer membrane. Bacteria with capsules, mycolic acid in walls, or no walls escape effects of some drugs.

Matrix in a biofilm.

Enzymes. Penicillinases & transacetylases.

Changes in protein side chains in wall.

Increase in rate of production in chemical inhibition scenario.

Pumps that actively efflux drugs.

Refuge. Some cells hide and are harder to get at. TB cells are in resistant host-created tubercle. Hide inside phagocytes (cryptic membrane package). Some are not in cells but in the interstitial fluid, avoid detection.

Reduced activity.


Living Beings are Crucibles for MABR Forms

Resistance genes can occur on plasmids or in main chromosome. Either way, rapidly disbursed to other cells.


R plasmids.

Integrons – jumping gene casette with its own insertion enzymes. Main chromosome. Copied every time cell divides.


Our Food Supply Source of ABR and of MABR strains.

Grow animals and produce at high density, use antibiotics prophylactically at low levels and for long duration. Selects for drug resistance. Evidence that drug resistant bacteria can get into humans in their food. Constant low level exposure to antibiotics as well?