Antimicrobial Agents and Therapy *Don’t need to memorize Structures Antimicrobial Agents and Therapy- Definitions (see Table 12.2)o Chemotherapeutic Drug : a chemical used in the treatment of disease Ex: Anti cancer drugso Antimicrobial Drug : a chemical used in the treatment of infectious disease Antibacterial, antiviral, antifungal, etc. o Antibiotics : a type of antimicrobial drug which is natural product of a living organism Prime drug What Organisms Produce Antibiotics?- Certain types of bacteria and Fungi - Phylum Actinobacteria o Gram (+), abundant in soil and water- The most common group known as: The Actinomyceteso General characteristics Most aerobic, chemoheterotrophs Many produce branching tube-like cells (hyphae) that often form interconnected networks (mycelia) Some produce sporesMany free living, a few are pathogensImportance of Actinomycetes- Free living forms common in soilso Streptomyces and antibiotic production!Number of antibiotics produced*Don’t need to memorize numbers MicroorganismsYEAR TOTALSTREPTOMYCETESRAREFORMSBACTERIAFUNGIBefore 19405 2 - 2 11945 88 10 2 25 511950 316 72 10 94 1401955 707 325 22 137 2231960 1275 760 40 181 2941965 1898 1177 75 223 4231970 2889 1745 136 328 6801975 4099 2361 250 518 9701978 4973 2769 396 567 1151Types of Antibiotics Produced- Don’t need to memorize-shows that the type is very specific ANTIBIOTICISOLATED FROM MICROORGANISM(Spectrum) Broad & Narrow ACTIVE AGAINSTBLASTICIDIN-SSTREPTOMYCES GRISEOCHROMOGENESFUNGICHLORAMPHENICOLSTREPTOMYCES VENEZUELAEGRAM POSITIVE & NEGATIVE BACTERIACYCLOHEXIMIDESTREPTOMYCES GRISEUSFUNGIERYTHROMYCINSTREPTOMYCES ERYTHREUSGRAM POSITIVE BACTERIAKANAMYCIN STREPTOMYCES KANAMYCETICUSGRAM POSITIVE & NEGATIVE BACTERIA,TUBERCULOSIS BACTERIASTREPTOMYCINSTREPTOMYCES GRISEUSGRAM POSITIVE & NEGATIVE BACTERIA, TUBERCULOSIS BACTERIANEOMYCINSTREPTOMYCES FRADIAEGRAM POSITIVE & NEGATIVE BACTERIA, TUBERCULOSIS BACTERIAAntibiotics• First antibiotics isolated from fungi and bacteria• Grown on petri plates • Noticed that one specific microbe couldn’t grow near another Antibiotics- The major drugs used to treat bacterial infections (antibiotics are antibacterial drugs)o A few work against some protozoa but mainly just bacteria o Not antiviral!- Many types are synthesized in labs as chemical derivatives of “natural” antibiotico Would just alter it to see if they could make it work betterPenicillin – the First Antibiotic• Isolated from the fungi Penicillium in 1930s by Alexander Fleming• Purified and used as a drug in 1941Impact of Antibiotics- Wartimeo Civil War 66% of all military deaths due to diseaseo WWI 54% of all military deaths due to diseaseo WWII 28% of military deaths due to diseaseAntimicrobial Agents and Therapy- Properties of Antimicrobial Drugso selective toxicity The drug has to be toxic to the microorganism but harmless to the patient o must be able to reach infected siteo must remain active at infected site One it gets to infected site must remain active there o others (see Table 12.1)Antibacterial Drug Target Sites Figure 12.2- General Modes of Actiono Static Drugs (Static effect) drug inhibits growth / replication of microbe immune system kills remaining microbeso Cidal Drugs (cidal effect) drug kills the microorganism often dose dependentTarget Sites & Specific Modes of Action- 1. Cell Wall Disruptiono Cell wall is the target for many different kinds of drugs o Most work by interfering with production of peptidoglycano Work best on young actively growing cells These are the cells that are producing a lot of their cell wall o Examples Penicillin - prevents protein crosslinks from forming Bacitracin - prevents subunits from being transported (exported) outside of the cell Target Sites & Specific Modes of ActionTarget Sites & Specific Modes of Action- 2. Cell Membrane Disruption (Layer that controls all movement in and out of cells) o If you mess up the membrane than the permeability is lost  Molecules that want in leak out, etc. o Due to similarities between all membranes, drugs tend to be more toxic to humans  Because all living cell membranes for most part have samestructure - So occasionally have drugs that kill bacteria very well, but can have toxic effects on our cell membrane o effective against all age cells and relatively inactive cellsTarget Sites & Specific Modes of Action- Cell Membrane Disruptiono Examples Antibacterial Drugs - Polymixins (Antiobiotics)o disrupts membrane surface by interacting with phospholipids of Gram (-) bacteriao Narrow spectrum  Antifungal Drugs (Both drugs interfere with sterols in cell membrane) - Polyenes (Poly=Most toxic to humans) o form complexes with sterol lipids in fungal cell membranes  abnormal openingso These are saved for very drastic cases because their so toxic- Imidazoleso Inhibit sterol synthesis, alter membrane permeability in fungal membraneso More Broadly Usedo Less toxic to people have fewer side effects o Ex: Antifungal sprays, reproductive tract fungi Target Sites & Specific Modes of ActionAntimicrobial Drugs - Specific Modes of Action- 3. Inhibiting Nucleic Acids (DNA/RNA)o Inhibit the unwinding of DNA molecule bacteria must unwind DNA molecule for replication and transcription Drugs block bacterial enzymes used in unwinding (DNA gyrases)- These drugs keep enzyme from doing its job  Example: Quinoloneso Inhibit RNA Polymerase Enzyme that makes RNA  Example: Rifampin- Used for people with tuberculosisAntimicrobial Drugs - Specific Modes of Action- 4. Protein Synthesis Disruptiono Drugs act on the mRNA-ribosome complexo Drugs which bind to 30s subunit Aminoglycosides - cause misreading of the mRNA- Work by making bacterial cell sticking to a very specific place on a subunit  Once there it throws off reading of genetic code  Tetracyclines - block attachment of tRNAs- Stick to small subunit  Keeps transfer RNA from coming in - No proteins are synthesized o Drugs which bind to 50s subunit Chloramphenicol - prevents peptide bond formation- Binds to big subunits  Then interferes with how the amino acid is linked together  Erythromycin (a macrolide)- prevents movement of ribosome along mRNA- Without proteins cell quickly dies (Ribosomes make the proteins) Antimicrobial Drugs - Specific Modes of Action- 5. Disruption of Metabolic Pathwayso Inhibit synthesis of nitrogenous baseso Drugs that interfere with