Lecture 11 Antimicrobial agents chemicals that are used to kill or inhibit the growth of bacteria First ones that were synthetic were thought up by Paul Ehrlich o Microscopist observed that stains could distinguish between bacterial and eukaryotic cells too Hypothesis selective toxicity might take up other chemicals differently Search for magic bullet would selectively kill disease causing bacteria o Chemical treatment of syphilis 1910 Salvarsan Synthetic antimicrobial chemical could selective kill bacteria over eukaryotic cells Treats infection and relieves diseases o This is a chemotherapeutic agent chemical used in therapy to treat diseases Before this people tried using metals to put directly on infection but this could be toxic His hypothesis was if stains can be differentially taken up by cells then perhaps chemicals could be taken up differentially by cells o Observing looking for bacteria to die Discovery of antibiotics o Antibiotics are a specific class of antimicrobial agents produced by other organisms usually microorganisms for example fungi produce some antibiotics today many antibiotics are produced by other bacteria o Alexander Fleming Studying the growth of bacteria Went away on vacation Spores from downstairs lab blew up onto plates and one grew a fungus and in the neighborhood of the fungus the growth of the bacteria was inhibited Observed inhibited growth Hypothesis fungus producing antimicrobial product Discovery of penicillin Antibiotics as a whole were new when penicillin was being patented people wondered if they d be useful on a large scale Penicillin became the antibiotic of choice in WW2 Infection killed more than the actual wound Tool to treat these infections Penicillin G natural natural form of the antibiotic o People modified it o For example methicillin semisynthetic Penicillins to be able to give people less with still having a treatment occur o Penicillin can be isolated from the fungi Terms o Acquired resistance resistance that develops through mutation or acquisition of o Antibacterial drug an antimicrobial drug that is used to treat a disease caused by new genes bacteria o Antibiotic a compound that is naturally produced by certain molds and bacteria that inhibits growth of or kills other microorganisms o Antimicrobial drug or antimicrobial A chemical that inhibits the growth of or kills microorganisms This term encompasses antibiotics and chemically synthesized drugs o Antiviral drug a drug that interferes with the replication of viruses All antiviral drugs are chemically synthesized none are antibiotics o Bactericidal drug an antimicrobial drug that kills bacteria o Bacteriostatic drug an antimicrobial drug that inhibits the growth of bacteria o Broad spectrum antimicrobial an antimicrobial that is effective against a wide range of microorganisms often including both gram positive and gram negative bacteria o Chemotherapeutic agent a chemical used to treat disease o Intrinsic resistance resistance due to an inherent characteristic of the o Narrow spectrum antimicrobial an antimicrobial that is effect against a limited microorganism range of microorganisms o R plasmid a plasmid that encodes resistance to one or more antimicrobial drugs o Therapeutic index a measure expressing the relative toxicity of a chemotherapeutic drug It is the lowest dose toxic to the patient divided by the does used for therapy Mechanisms of action o Target biological processes antimicrobials effect something the cells need to do Cell wall synthesis Cell membrane stability DNA synthesis RNA synthesis Protein synthesis Metabolism Substrate transport Depending on the chemical they effect different parts of the cell Very rarely does one chemical have more than one effect on a different parts of the cell Usually what the antimicrobial or antibiotic does is specific to a certain process Ways the antimicrobials effect the cell o Inhibition of cell wall synthesis Penicillins cephalosporins vancomycin bacitracin isoniazid ethambutol o Inhibition of protein synthesis they are the biological catalyst if you stop synthesizing new ones the cell cannot divide ability to do functions goes away Aminoglycosides tetracyclines chloramphenicol macrolides o Inhibition of pathogen s attachment to or recognition of host Arildone pleconaril o Inhibition of DNA or RNA synthesis Actinomycin nucleotide analogs quinolones rifampin o Inhibition of general metabolic pathway Sulfonamides trimethoprim dapsone o Disruption of cytoplasmic membrane Polymyxins polyenes antifungal Cell walls and antibiotics o How the cell wall is formed Sugar molecules are attached to a protein carrier The peptides are added to the sugar molecule These chemicals are then flipped to the other side of the cell then attached to the cell wall Cross linking is done and the cell wall grows like that o Penicillin and inhibition of cell wall formation The first 2 steps are allowed to continue however when it comes across on the cell membrane the penicillin prevents the cross linking So first thing it does is weaken the cell wall then it also stimulates these other proteins called autolysines that degrade the cell wall that is already there o Vancomycin also inhibits cell wall formation Again it allows the first two steps of cell wall formation to occur but then it inhibits cross linking so there is only strings of sugar trying to go around the cell o Vasatracin Allows first three steps to occur However it stops the proteins that moves the sugar molecules and peptides across the way from being recycled So it stops the cycle there basically taking away the machinery that builds the cell wall cell does not grow any longer Another example of a synthetic antimicrobial sometimes referred to as sulfa drug sulfonamide it inhibits an enzymatic pathway that is an Antimicrobial effecting pathway o Organisms take up paraenzymbetaway And they convert it to folic acid which is then used in the synthesis of purines and pyrimidine nucleotides these are used in the synthesis of DNA and RNA o Sulfonamide binds to the active site of the enzyme that converts the paba to dihydrofolic acid o This is a competitive inhibitor of this enzyme o Once there is enough of sulfa in the environment this reaction stops and the cells cannot make the basis for DNA o Example antimicrobial effecting biological pathway Nalidixic acid synthetic antimicrobial o Chlorquine drug used in the treatment of malaria o Specifically inhibits the DNA structure Gyrase o DNA