Transcript Antibiotics
Plants and Fungi Used to Treat Infectious Disease Infectious Disease • World wide, infectious disease is the number one cause of death accounting for approximately onehalf 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 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 Overview • Antibiotics from fungi • Antimalarials from plants • Other antimicrobials from plants 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 Discovery of Penicillin • Folk treatments for wounds • 19th Century observations of antibiosis by Penicillium spp – Roberts - 1874 – Tyndall - 1881 – Others • Flemming - 1928 Sir Alexander Fleming Fleming’s Petri Dish - Penicillium notatum killed the culture of Staphylococcus aureus 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 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 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 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 Drawbacks • Resistance - evolution of penicillinresistant bacteria • Allergies - Penicillin is the most frequent cause of anaphylaxis 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 b Lactam Basic Structure 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 Penicillin-G Penicillin-G • Still an important antibiotic • Disadvantage has been that it is unstable in acid conditions • Given by injections - otherwise stomach acids would destroy 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 Penicillin-V phenoxy methyl penicillin 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 R=H 6-APA Ampicillin Methycillin 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 Resistance due to b-Lactamase 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 Cephalosporin Clinically Important Antibiotics Antibiotic Producer organism Activity Site or mode of action Penicillin Penicillium chrysogenum Gram-positive bacteria Wall synthesis Cephalosporin Cephalosporium acremonium Broad spectrum Wall synthesis Griseofulvin Penicillium griseofulvum Dermatophytic fungi Microtubules Bacitracin Bacillus subtilis Gram-positive bacteria Wall synthesis Polymyxin B Bacillus polymyxa Gram-negative bacteria Cell membrane Amphotericin B Streptomyces nodosus Fungi Cell membrane Erythromycin Streptomyces erythreus Gram-positive bacteria Protein synthesis Neomycin Streptomyces fradiae Broad spectrum Protein synthesis Streptomycin Streptomyces griseus Gram-negative bacteria Protein synthesis Tetracycline Streptomyces rimosus Broad spectrum Protein synthesis Vancomycin Streptomyces orientalis Gram-positive bacteria Protein synthesis Gentamicin Micromonospora purpurea Broad spectrum Protein synthesis Rifamycin Streptomyces mediterranei Tuberculosis Protein synthesis