I. Discovery of antibiotics: History

The systematic search for effective chemotherapeutic agents began in the laboratory of Paul Erlich who discovered that an arsenic compound, which he called Salvarsan, had some therapeutic value in treating syphilus. Some 20 years later a dye, protosil, was found to have therapeutic value. Dye was split in blood to the active ingredient, sulfanilamide, the first sulfa drug to be discovered

Fleming, 1929, is credited for discovery the first antibiotic, Penicillin. How was penicillin discovered? In 1940's Chain and Florey chemically purified and characterized penicillin

How does an antibiotic differ from a chemotherapeutic agen?

II. Choosing the best chemotherapeutic/antibiotic agent: No single anitmicrobial durg is safe in all patients or effective against every infectious disease. The factors that influence the therapeutic value of an antimicrobial drug are:

• Selective toxicity- drug only valuable if it shows selective toxicity to microbe, and produces no or as few undiserable side effects. Selective toxicity is a relative terms since many drugs are toxic at high concentrations. The toxicity of a given drug is expressed as the the therapeutic index of the drug; the lowest doese toxic to the patient divided by the dose typically used for treatment. Is it better to have a high or low therapeutic index?
  
• Bactericidal/Bacteriostatic- drugs may kill microbes (bactericidal) or inhibit, bacteriostatic, their growth.
  
• Spectrum of Activity- Drugs are either narrow-spectrum or broad-spectrum according to the range of microbes they are usually effective agents. What is one of the downsides of giving a broad-spectrum antibiotic to treat a bacterial disease?
  
• Tissue Distribution, metabolism, and excretion of Drug- antibiotics have no therapeutic value unless they reach the site of infection in concentration high enough to kill or inhibit the growth of the microbe. Is drug sensitive to acid, are you trying to treat an intracellular pathogen (Chlamydia or Rickettsia), how fast is drug metabolized by body (example, intramuscular injections of penicillin may contain procaine or benzathine to delay absorption, and thus maintain concentration in blood for long times.
  
• Adverse Effects- some people develope hypersensitivities or allergies to certain drugs that can be life threatening (anaphylactic shock). Aminoglycosides can damage kidneys, impair balance, and even cause irreversible deafness. Chloramphenicol can cause aplastic anemia (inability to make red and white blood cells). Most common adverse effect is causing secondayr infections (super infections). Patients who take a broad-spectrum antibiotic may develop the life-threatening disease know an antibiotic associated colitis, caused by a toxin-producing strain of Clostrium difficile. when normal flora killed C. difficile can proliferate.
  
• Resistance to Drug- Some bacteria are inherently resistant (intrinsic resistance) to the effects of a particular durg. Why is Mycoplasma peumoniae resistant to the b-lactam family of antibiotics (penicillin and cephalosporin)? Some bacteria may acquire resistance (see below).
  
• Drug Interactions- Some drug combinations antagonize one another. Why does tetracycline antagonize the action of penicillin?
  
• Cost- new drugs cost about 20 times more than an older drug.

III. Mechanisms of Action of antibiotics:

• Target cell wall- How does changing the structure of a b-lactam like penicillin change its propeties?
  
• Target bacterial protein synthesis- How does the mechanism of action of aminoglycosides (streptomycin, gentamicin, kanamycin) differ from that of the tetracyclines and that of erythromycin, clindaycin, and chloramphenicol. Why is chloramphenicol the most widely used antibiotic in the world?
  
• Targe bacterial metabolism- How do sulfa drugs interfer with metabolism of folic acid and why does it not affect us?
  
• Target nucleic acid- What is the mechanism of action of rifampin and nalidixic acid? Would you expect these drugs to have a higher or lower therapeutic index compared to penicillin?
  
• Target cell membrane- polymixins increase permeability of membrane. Because of toxicity used more as a topical antibiotic (burn patients).

IV. How can one determine the sensitivity of a bacterium to an antibiotic?

V. Development of resistance

• Drug-inactivating enzymes- how does penicillinase work?
• Modify the target molecule- change chemistry of penicillin-binding protiens of proteins in 70S ribosome.
• Decrese uptake of Drug- change chemistry of porin in Gram-negative bacteria.
• Increase elimination of drug- antiport
• acquisition of antibiotic resistant genes. What are R-plasmids and how may they be transfer to another bacterium?

VI. How effective are antibiotics in treating viral infections?