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Drugs, Microbes, Host--The Elements of Chemotherapy
Antibacterial antibiotics

Chapter 12 - MicrobiowikiChapter 12 - Microbiowiki

Penicillin- Derived from the mold Penicillium. Called a "semi-synthetic" when produced through microbial fermentation, and then chemically altered. Penicillin is still the drug of choice for gram-positive bacteria.
  • Semisytnhetic penicillins (ampicillin, carbenicillin, and amoxicillin) have a broader spectrum.
File:PenicillinPSAedit.jpg
Alexander Fleming
:


Chapter 12 - Microbiowiki

In 1928 he was studying staphylococci. He was already known as a great researcher, but also as a careless lab technician. After being away he noticed that many of his lab cultures had grown fungus around them. He threw them into disinfectant, but when someone asked what he had been working on he retrieved them. It was then that he saw a zone around the invading puss where bacteria could not seem to grow. He continued to isolate and extract from moldy bread and was able to identify it as being Penicillin. He began to investigate its antibacterial affect especially on gram-positive bacteria. Fleming published his findings, but not much attention was given to it. He found that is was too hard to isolate the antibiotic agent. Soon after Fleming had given up his research with Penicillin, Ernst Chain and Howard Florey began researching and mass producing it. When D-Day arrived they had enough to treat all the wounded soldiers.

Cephalosporins- Relatively new, but are the most commonly administered group of antibiotics. Produced from the mold Cephalosporium. Similar in structure and function of penicillins, but have a few advantages like: relatively large spectrum, resistant to penicillinases, fewer allergic reactions. There are 3 generations with each more effective than the last. These drugs will have "cef, ceph, or kef" in thier names. Most are given parentally, but some are given orally.

Aminoglycosides- Is made from Streptomyces (filamentous fungi-like soil bacteria.) Relatively broad spectrum because they inhibit protein synthesis.
  • Streptomycin & gentamicin are newer and less toxic. They are good to treat gram-negative rods like Escherichia, Psuedomonas, Salmonella, Shigella.
Tetracycline antibiotics- Semisynthetics derived from a species of Streptomyces. Blocks protein synthesis, effective against a wide variety of bacteria. Used to treat several types of STD's as well as Rocky Mt Spotted Fever, Lyme Disease, typhus, cholera, acne.
  • Side Effects: Toxic to growing teeth and bones, causes birth defects, can cause GI upset, sensitivity to sunlight, and can discolor tooth enamel. Can cause a superinfection, and should never be given to pregnant women, or children. Any woman taking a Tetracycline antibiotic would also be on some sort of birth control. Tetracycline can cause severe birth defects.
Chloramphenicol- Is a Streptomyces antibiotic, is a broad-spectrum, also blocks protein synthesis. Very toxic and only used when other options are not available.
New classes- Always looking for new antibiotics.

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

Interferon- Anti viral therapy. It is a natural compound produced by many types of cells. It's activity is species specific. It appears to act by interfering with translation functions once the virus has entered the cell. It is produced by infecting human lymphocytes, lymphoblasts, or fibroblasts with a virus or exposing them to a chemical inducer. The cells respond by releasing interferon into the medium, and the material is then purified by a number of complex chemical steps. Alternatively, the gene for interferon production can be inserted in bacteria, allowing large-scale and efficient production of this complex protein (Cecil Textbook of Medicine,1988).

CHARACTERISTICS OF THE IDEAL ANTIMICROBIAL DRUG
  • Selectively toxic to the microbe but non toxic to host cells
  • Microbicidal rather than microbiostatic
  • Relatively soluble and functions even when highly diluted in body fluids
  • Remains potent long enough to act and is not broken down or excreted prematurely
  • Not subject to the development of antimicrobial resistance
  • Complements of assists the activities of the host's defenses
  • Remains active in tissues and body fluids
  • Readily delivered to the site of infection
  • Not excessive in cost
  • Does not disrupt the host's health by causing allergies or predisposing the host to other infections
  • Quinine
  • Inhibition of cell wall synthesis
  • Inhibition of nucleic acid synthesis, structure or function
  • Inhibition of protein synthesis
  • Disruption of cell membrane structure or function


Pathogen Targets of Antimicrobial Drugs
cell wall cell membrane ribosomes DNA/RNA Metabolic Pathway
penicillins macrolides erythromycin fluoroquinolones sulfa
cephalosporins azoles chloramphenicol cyclovirs trimethoprim
bacitracin amantidine aminoglycosides flucytosine
vancomycin
tetracycline rifampin

Here is another table organizing the information of pathogen targets of antimicrobial drugs in a different way


Drugs Organized by Origin and Structure

Beta-lactams
Aminoglycosides
Tetracyclines
Chloram
phenicols
Sulfonamides
Names Penicillins Cephalosporins Streptomyces derivatives aureomycin
terramycin

sulfa drugs
Brand/Generic names Amoxicillin, Trimox, Penicillin VK Keflex, Cephalexin


septra, bactrim
sulfisoxazole,
silver sulfadiazine,
trimethoprim
Cell Target
cell wall cell wall protein synthesis protein synthesis protein synthesis metabolic pathway
Side-effects
renal failure,
neutropenia
thrombocyto-penia,rash,
seizures
renal failure
seizures,
renal failure,vertigo,
neuropathy,deafness,
respiratory arrest,
photo-sensitivity,
rash,
irreversible
damage to
bone marrow,
anemia
allergic rash,
renal failure,
goiter,anemia,

Drugs that affect the bacterial cell wall
Most bacterial cell walls contain a rigid girdle of peptidoglycan (protects cell from rupture in hypotonic environments).
Penicillin and cephalosporin block synthesis of peptidoglycan by reacting with the enzymes required to complete this process, causing the cell wall to lyse.
Most of these drugs are active only in young, growing cells - old, inactive, or dormant cells don't synethize peptidoglycan.
• Penicillins do not penetrate the outer membrane and are less effective against gram-negative bacteria.
• Broad-spectrum penicillins and cephalosporins can cross the cell walls of gram-negative bacteria.

Test yourself:
- What drugs affect the bacterial cell wall? How do they do this?
- Why aren't penicillin and cephalosporins effective against old or dormant cells?
- Are penicllins and cephalosporins considered bactericidal or bacteristatic? Why?
- Are penicillins effective against gram-negative bacteria?

Drugs that inhibit nucleic acid synthesis
May block synthesis of nucleotides, inhibit replication, or stop transcription
Sulfonamides and trimethoprim block enzymes required for tetrahydrofolate synthesis needed for DNA & RNA synthesis.
• These types of drugs work by: competitive inhibition – drug competes with normal substrate for enzyme’s active site, or synergistic effect – an additive effect, achieved by multiple drugs working together, requiring a lower dose of each

Test yourself:
- How do drugs inhibit nucleic acid synthesis? (Three ways)
- What drugs inhibit nucleic acid synthesis?
- Two drugs blcok enzymes needed for DNA and RNA synthesis. What are they, and how do they work?
- What two methods do DNA-RNA-inhibiting drugs work by?


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.
Aminoglycosides (streptomycin, gentamicin) insert 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.

Test yourself:
- How do these drugs block protein synthesis?

- What eukaryotic structure can these drugs harm?

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.

Test yourself:
- Why does a cell with a damaged membrane die?
- Drugs that damage bacterial cell membranes have specificity based on what?
- What drugs disrupt cell membrane function?
- Which drug works well against gram-negative bacteria?

- Which drugs work well against fungi?

Antimicrobial Drugs that effect metabolic pathways
Sulfonnamides and trimethopim are drugs that act by mimicking the normal substrate of an enzyme in a process called Competitive inhabition. They are supplied to the cell in high concentrations to ensure that a needed enzyme is constantly occupied by the metabolic analog rather than the true substrate of the enzyme. As the enzymeis no longer able to produce a needed product, cellular metabolism slows or stops.Sulfonames and trimethoprim interfere with folate metabolim by blocking enzymes required for the synthesis of tetrahydrofolate, which is needed by bacterial cells for the synthesis of folic acid and eventual production of DNA and RNA and amino acids.

Q: The golden age of antibiotics began in 1928 with Sir Alexander Fleming's discovery of an antibacterial compound he called what?
a. Arsenic
b. Penicillin
c. Sulfonamide
A: Penicillin

Interactions Between Drugs and Microbes
Antimicrobial drugs are used in two different ways. To disrupt the cell processes of bacteria, fungus, or protozoa, or to inhibit virus replication. Drugs should be able to kill microbial cells with out doing any harm to their host cells. This is called selective toxicity. Penicillin is an example of a drug with selective toxicity. It blocks synthesis of the cell wall in bacteria and has low toxicity and little effect on the host cell wall.

Q: Which of the following is not a category of antimicrobial drugs?
a. Those that inhibit protein synthesis
b. Those that interfere with cell membrane structure and function
c. Those that inhibit mRNA processing in the nucleus
A: Those that inhibit mRNA processing in the nucleus

Q: Antimicrobials that block nucleic acid synthesis may act in all but which of the following manners?
a. They can block DNA transcription
b. They can block the synthesis of DNA and RNA nucleotides
c. They can inhibit the action of tRNA
A: They can inhibit the action of tRNA

Interactions Between Drugs and Host:
During an infection the microbe is living in or on a host; therefore the drug is administered to the host though its target is the microbe. So with that in mind the effect of the drug on the host must always be considered. There are three major side effects of antimicrobials are toxicity to organs, allergic reactions, and problems resulting from suppression or alteration of normal flora.

Toxicity to Organs:
Drugs can affect the following organs: the liver (hepatotoxic), kidneys (nephrotoxic), gastrointestinal tract, cardiovascular system and blood-forming tissue (hemotoxic), nervous system (neurotoxic), respiratory tract, skin, bones, and teeth.

Allergic Responses to Drugs:
One of the most frequent drug reactions is heightened sensitivity, or allergy. This reaction occurs because the drug acts as an antigen and stimulates an allergic response.

Suppressing and Alteration of the Microflora by Antimicrobials:
Most normal healthy body surfaces provide numerous habitats for virtual "garden" of microorganisms. These normal colonists are called flora or microflora and is mostly of harmless or beneficial bacteria, but a small number can potentially be pathogens. Antimicrobials that destroy most but not all normal flora allow the unaffected normal flora to overgrow, causing a superinfection.

Considerations in Selecting an Antimicrobial Drug
The three major considerations necessary to choose an effective antimicrobial are the nature of the infecting microbe, the microbe's sensitivity to available drugs, and the overall medical status of the infected host.
The effectiveness of antimicrobial drugs is being compromised by several alarming trends: inappropriate prescription use of broad-spectrum instead of narrow-spectrum drugs, use of higher-cost drugs, sale of over-the-counter antimicrobials in other countries, and lack of sufficient testing before prescription.

External links to drug companies describing various antibacterial drugs

Drug Resistance
You can listen to a podcast from the CDC discussing extensively drug resistant tuberculosis (XDR TB).

Antibacterial Antibiotics

Penicillins: large and diverse group. Can be made in a lab. Major source is Penicillium chrysogenum.

Cephalosporins: the majority of all antibiotics prescribed. Able to alter beta-lactam ring. Broad spectrum and resistant to most penicillin's. Cause fewer allergic reactions. Three generations.

Other Beta-lactam Antibiotics

Imipinem: broad spectrum drug used for infections with aerobic and anaerobic pathogens.

Aminoglycosides: made up of 2 or more sugars and an aminocyclitol ring. Broad spectrum, inhibits protein synthesis. Used on aerobic gram-negative rods and some gram-positive bacteria.

Tetracycline antibiotics: Broad spectrum. Block protein synthesis.

Chloramphenicol: Potent and very broad spectrum. Blocks formation of peptide bonds. Is not derived from a natural source. Very toxic. May cause irreversible damage to bone marrow.

Other Streptomyces antibiotics
Bacillus antibiotics
-new classes

Therapeutic Benefits of Food
  • Yogurt has been shown to control Staphylococcus infections
  • Garlic extract can inactivate viruses and destroy bacteria
  • Cranberry juice research indicates that it can keep E.coli from attaching to tissues
  • Zinc keeps the common cold virus from attaching
  • Apple juice, fruit juices and tea contain natural antiviral substances

flashcards for this chapter are at www.flashcardexchange.com under kevin youngs micro chapter 12



Questions: Q&A Page~~Home Page~~Top of Page

1. When did Sulfa "hit" the market?
a. 1920's
b. 1940's
c. 1950's
d. 1930's

2. During WW II which country started "rediscovering" the effects of Penicillin?
a. England
b. Germany
c. United States
d. France
e. none of the above

3. Who actually discovered compound 606, also known as salvarsan?
a. Robert Koch
b. Louis Pasteur
c. Alexander Fleming
d. Paul Ehrlich

4. A compound synthesized by bacteria or fungi that destroys or inhibits the growth of other microbes is a/an
a. Synthetic drug
b. antibiotic
c. antimicrobial drug
d. competitive inhibitor

5. Which of these are involved in osmotic lysis of the cell well?
a) Penicillins
b) Cephalosporins
c) Cycloserine
d) Vancomycin
e) All of the above
f) None of the above

6. Which of these drugs do not affect the nucleic acid synthesis?
a) Sulfonamides
b) Trimetoprim
c) Polymyxins
c) Chloroquine
d) Quinolones
e) acyclovir

7. Which drugs are competitive inhibitors by occupying the binding site of the enzyme and blocking the substrate from the site?
a) Sulfonamides (sulfa drugs) and trimethoprim
b) Cycloserine and vancomycin
c) Amphotericin B and nystatin


8. Do beta-lactams drugs destroy all of the targeted bacteria cell wall? If not, then why? Why are human cells not effected?

9. What was the first known treatment for syphilis?
a) soybean curd applied topically
b) myrrh and frankincense
c) arsenic and mercury
d) penicillin

10. Which is not a characteristic of an ideal drug?
a) microbicidal and microbiostatic
b) remains potent long enough to act
c) readily delivered to the site of infection
d) doesn’t lead to microbial resistance

11. Chemotherapeutic agents are described with regard to:
a. origin
b. range of effectiveness
c. naturally produces
d. chemically synthesized
e. all of the above

12. Which bacteria would be the best the the drug spectrum for both gram + and gram -?
a. narrow spectrum
b. medium spectrum
c. broad spectrum

13. What inhibits DNA unwinding enzymes or helicases?
a. Penicillin
b. Chloroquine
c. Acyclovir
d. Azidothymidine

14. Tetracycline block the attachment of:
a. mRNA
b. inhibition of 30s subunit ribosome
c. tRNA
d. inhibition of 50s subunit ribosome

15. This was the first penicillin that became the patent for all other "cillins":
a. V
b. G
c. A
d. C

16. The adverse effect of tetracycline given to young children is...
a. allergies
b. joint damage
c. discoloration of teeth
d. dependency on drug

17. Which of these drugs com



18. Which drug is able to alter the beta-lactum ring?
a. penicillin
b. cephalosphorins
c.aminoglycosides
d.tetracycline

19. Yogurt has been shown to control_________.
a. alergies
b. fungus
c. E.coli
d. staphylococcus

20. Most antiheminthic drugs function by:
a. weakining the worms so they can be flushed out by the intestine
b. infibiting worm metabolism
c. blocking the absorption of nutrients
d. inhibiting egg production

21. A patient has a red circular rash on his arm and fever, malaise, and joint pain. The most appropriate treatment is:
a. penicillin.
b. chloroquine.
c. anti-inflammatory drugs.
d. rifampin.
e. no treatment.

22. Some of the benifits of interferon are:
a. reduce the time in healing
b. preventing some symptoms
c. slowing the progress.
d. all of the above.


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