Slide 1The First AntibioticSlide 3Some Definitions…Slide 5Slide 6Slide 7Slide 8Slide 9Examples Of Unique Targets And Relevant AntibioticsSide Effects of AntibioticsNormal flora, commensalsUnique Targets In FungiDrug resistanceBacterial Drug ResistanceBacterial geneticsTransformation in bacteriaImportant observations from Griffith’s experimentSlide 19Mechanisms Of Drug ResistanceSlide 21Slide 22Mechanisms of gene transfer in bacteriaMechanisms of gene transfer in bacteria2. Conjugation (nonconventional bacterial sex)3. Transduction (by bacteriophage)Plasmids / R-factorsRecombinant DNA TechnologyTransgenicsCloning an animal (nuclear transfer)The Human Genome sequencing ProjectWho is winning? The Super BugAntibiotic Action & GeneticsObjectives:1. Describe the discovery of antibiotics.2. Describe the concept of antibiotic target and list the targets of major antibiotics in use today.3. Describe the action of antibiotics.4. Describe who made what major discoveries in bacterial genetics and explain how genes are altered and transferred between bacteria.5. Provide examples of how modern genetic discoveries are impacting the practice of medicine.1The First AntibioticAlexander Fleming (1881-1955) discovered Penicillin•Sir Alexander Fleming was a Scottish biologist and pharmacologist. –He discovered the antibiotic substance penicillin from the fungus Penicillium for which he shared a Nobel Prize–He also discovered the antibacterial substance lysozyme which is present in human tears and saliva•Estimated >200 million lives have been saved because of his discovery Fleming2•In 1928, Fleming discovered penicillin by accident•Efforts to produce large amounts of the mold failed for the next 10 years.•Thanks to the combined efforts of other scientists (Flory & Chain), penicillin was available in quantity to treat Allied soldiers wounded on D-Day (June, 1944) and thereafter.•Fleming, Flory and Chain won the Nobel Prize for Medicine in 1945.Fleming observed that a plate culture of Staphylococcus had been contaminated by a blue-green mold (Penicillium mold) and that there were no colonies of bacteria growing adjacent to the mold.moldStaphylococcus3Some Definitions…•Antibiotic: against living organism•Antimicrobial: against microbe•Narrow spectrum: effective against only a limited range of organisms Eg. Penicillin is effective against mostly Gram (+) bacteria •Broad spectrum: refers to an antibiotic with activity against a wide range of organismsEg. Amoxicillin is effective against both Gram (+) and Gram (-) bacteria4•Bactericidal (Cidal): Drug that completely destroys bacteria–Eg.- Cell Wall antibiotics like Penicillin •works by irreversible binding to active site of enzymes that link peptidoglycan molecules.5Peptidoglycan subunits•N-acetylglucosamine (NAG)•no peptide linkage•N-acetylmuramic acid (NAM)•with peptide linkage•Alternating subunits form PG layerPeptide linkagePolysaccharide backboneNAMNAG6As the bacterial cell grows, penicillin prevents the formation of the NAM-NAM peptide linkage during PG synthesisCell bursts from osmotic pressureWorks best for Gram-positive bacteria•Bacteriostatic (static) : Drug which stops cell growth–Eg. Erythromycin•Drug binds to subunits of bacterial ribosomes and stops bacterial protein synthesis which then stops growth of bacteria without destroying themBacteriostaticBactericidalAgar plate inoculated with bacteria that have been treated with cidal and static antibiotics BACBacteriostaticBactericidalNo antibiotic(Control)ControlAntibiotics are often derived from microbial species•Semisynthetic: A molecule derived from a biological source and manipulated in the laboratory to improve characteristics•Selective toxicity: Toxic to one thing but not another.–A good antibacterial drug should be highly toxic to bacteria but non-toxic, or very little toxicity to humans •Unique target: Basis for selective toxicity–A site in pathogen that is infecting the patient that drug needs to work specifically that is not present in the patient –Example, penicillin targets peptidoglycan (PG) which is present in bacteria only–A reason we need to compare prokaryotes (bacteria) and eukaryotes (human) in detail•Prophylaxis: Preventative measures–Example, if a patient has a history of rheumatic fever, you would treat prophylactically with antibiotics before a dental or surgical procedure9Examples Of Unique Targets And Relevant AntibioticsCell Wall Synthesis inhibitors (Cidal)•Beta Lactams•Penicillins•Cephalosporins•Vancomycin•BacitracinCell Wall Synthesis inhibitors (Cidal)•Beta Lactams•Penicillins•Cephalosporins•Vancomycin•BacitracinPlasma membrane inhibitors (Cidal)•PolymyxinsPlasma membrane inhibitors (Cidal)•PolymyxinsDNA Synthesis inhibitors (Cidal) •Quinolones•MetronidazoleDNA Synthesis inhibitors (Cidal) •Quinolones•MetronidazoleRNA polymerase inhibitor (Cidal)•RifampinRNA polymerase inhibitor (Cidal)•RifampinFolic acid synthesis Antimetabolites (Static) •Folic acid synthesis inhibitors•SulfonamidesAntimetabolites (Static) •Folic acid synthesis inhibitors•Sulfonamides10Protein Synthesis inhibitors (Static)•Erythromycin•Chloramphenicol•TetracyclineProtein Synthesis inhibitors (Static)•Erythromycin•Chloramphenicol•TetracyclineSide Effects of AntibioticsOf the most common antibiotics used:11•Organ toxicity•Vancomycin •neurotoxic and nephrotoxic•Chloramphenicol •Supresses bone marrow function•depresses immune system•Bacitracin •Nephrotoxic; only used as topical agent•Tetracycline•Complexes with Calcium and causes abnormalities in bone and teeth•Avoid prescribing to children and pregnant women•Organ toxicity•Vancomycin •neurotoxic and nephrotoxic•Chloramphenicol •Supresses bone marrow function•depresses immune system•Bacitracin •Nephrotoxic; only used as topical agent•Tetracycline•Complexes with Calcium and causes abnormalities in bone and teeth•Avoid prescribing to children and pregnant women•Allergies•Penicillin •Hypersensitivity (anaphylaxis) which may lead to shock and death•All drugs can cause allergies (have to check with patient)•Allergies•Penicillin •Hypersensitivity (anaphylaxis) which may lead to shock and death•All drugs can cause allergies (have to check with patient)Hives due to penicillin allergyGraying of teeth: tetracyclineNormal flora, commensals•The human commensal flora is