1. Plants and Fungi Used to Treat Infectious Disease

2. Infectious Disease
World wide, infectious disease is the number one cause of death accounting for approximately one-half of all deaths in tropical countries
Infectious disease mortality rates are actually increasing in developed countries, such as US
Infectious disease underlying cause of death in 8% of deaths occurring in US

3. Terms
Antimicrobial = a substance which destroys or inhibits the growth of microorganisms
Antiseptic = a substance that checks the growth or action of microorganisms especially in or on living tissue
Antibiotic = a substance produced by or derived from a microorganism and able to inhibit or kill another microorganism

4. Overview Antibiotics from fungi Antimalarials from plants
Other antimicrobials from plants

5. Penicillin By-product of certain Penicillium species
Inhibits the growth of gram-positive bacteria
Blocks wall synthesis in bacteria and results in death of the bacterial cell by lysis
Surpassed known therapeutic agents by suppressing bacterial growth without being toxic

6. Discovery of Penicillin
Folk treatments for wounds
19th Century observations of antibiosis by Penicillium spp
Roberts
Tyndall
Others
Flemming

7. Sir Alexander Fleming

8. Fleming’s Petri Dish - Penicillium notatum killed the culture of Staphylococcus aureus

9. Zone of Inhibition
Around the fungal colony is a clear zone where no bacteria are growing
Zone of inhibition due to the diffusion of a substance with antibiotic properties from the fungus

11. Research continues
In 1939, - Oxford University Howard Florey and Ernst Chain
1941 first human tests
1941 research moved to the US
USDA labs in Peoria Illinois
Summer 1943 Penicillium chrysogenum
D-Day 1944
1945 Nobel Prize

12. Start of Synthetics
Soon after World War II, the pharmaceutical industry developed chemically altered versions of the penicillin molecule
Modified penicillins provided for greater stability, broader anti-bacterial activity, and also oral administration which would permit home use of antibiotics

13. Penicillin Today Still the most widely used antibiotic
Still the drug of choice to treat many bacterial infections
Scientists have continued to improve the yield of the drug
Present day strains of P. chrysogenum are biochemical mutants that produce 10,000 times more penicillin than Fleming's original isolate

14. Drawbacks Resistance - evolution of penicillin-resistant bacteria
Allergies - Penicillin is the most frequent cause of anaphylaxis

15. Synthesis of Penicillin
Penicillin - one of a family of b-Lactam antibiotics
b-Lactams produced by asexual fungi, some ascomycetes, and several actinomycete bacteria
b-Lactams are synthesized from amino acids valine and cysteine

16. b Lactam Basic Structure

17. Penicillins
When penicillin first isolated, it was found to be a mixture of various penicillins
Different R groups attached to the molecule
When large scale production began, it was found that by adding phenylacetic acid to the medium, the penicillin was all one type -penicillin-G

18. Penicillin-G

19. Penicillin-G Still an important antibiotic
Disadvantage has been that it is unstable in acid conditions
Given by injections - otherwise stomach acids would destroy

20. Penicillin-V
The addition of phenoxyacetic acid to the culture medium gives penicillin-V
This is not as active as penicillin-G, but it is acid stable and can be given by mouth
There are many other naturally occurring penicillins but these are still clinically very important

21. Penicillin-V
phenoxy methyl penicillin

22. Semi-Synthetic Penicillins
A strain of Penicillium chrysogenum found that produced large amounts of 6-amino penicillanic acid (6-APA)
6-APA lacked antibiotic activity but it could be used to add a variety of side chains and create semi-synthetic penicillins
methicillin and ampicillin
Semi-synthetics have made penicillins a more versatile group of antibiotics

23. R=H
6-APA
Ampicillin
Methycillin

24. Mode of Action
b-lactam antibiotics inhibit formation of the bacterial cell wall by blocking cross-linking of the cell wall structure
Bind to PBP – penicillin binding proteins in cell membrane that function as transpeptidases
Inhibit transpeptidases, which catalyze the final cross linking step in the synthesis of the peptidoglycan cell wall
Result: bacterial wall is weakened and cell bursts from osmotic pressure

25. Resistance due to b-Lactamase

26. Cephalosporin
In 1948 Giuseppe Brotzu identified a compound produced by Cephalosporium acremonium that was an effective treatment for gram-positive infections as well as some gram-negative ones such as typhoid
Brotzu sent a culture of this fungus to Florey. The team at Oxford once again isolated the active compound which they named cephalosporin
Today a whole class of cephalosporins

27. Cephalosporin

28. Clinically Important Antibiotics