Lecture 26 27 Chapter 20 THE HISTORY OF CHEMOTHERAPY chemotherapy the use of drugs to treat a disease basis provided by Paul Ehrlich 04 14 2015 antimicrobial drugs drugs that interfere with the growth of microbes within a host antibiotic a substance produced by a microbe that in small amounts inhibits another microbe first antibiotic was discovered by Alexander Fleming o Penicillium notatum mold inhibited Staphylococcus aureus o Antiobiotic named penicillin Howard Florey and Ernst Chain performed first clinical trials of Penicillin in 1940 Replaced original strain with a more powerful strain selective toxicity a drug that kills harmful microbes without damaging the host has this should affect microbial physiology that does not exist in humans o ie peptidoglycan difference in ribosome structure or biochemical pathways that we don t have side effects at high concentration o chloramphenicol interferes with eukaryotic ribosomes which can interfere with red blood cell development o can cause allergic response more than half of our current antibiotics are a species of Streptomyces most antibiotics discovered today are discovered through soil samples most antibiotics are natural but then modified to increase efficacy or decrease toxicity to humans THE SPECTRUM OF ANTIMICROBIAL ACTIVITY easy to find an antimicrobial agent if the microbe is prokaryotic because the cell walls differ dramatically narrow spectrum of microbial activity a small range of different microbial types a drug will affect ie penicillin G affects gram positive but very few gram negative broad spectrum antibiotics antibiotics that affect a broad range of gram positive and gram negative bacteria advantage saves time disadvantage kills many normal microbiota o can create superinfection pathogens that are resistant to antibiotics selective toxicity can be due to LPS outer layer of gram negative bacteria and the porins that form water filled channels across this layer THE ACTION OF ANTIMICROBIAL DRUGS bactericidal antimicrobial drugs that kill microbe directly inhibit cell wall synthesis only effective if organism builds new cell wall para bacteriostatic antimicrobial drugs that prevent the growth of the organism CANNOT KILL ORGANISM Immune system removes infection inhibiting cell wall synthesis weakens the cell wall o natural penicillin pencillin prevents the synthesis of intact peptidoglycan which penicillin extracted from the mold Penicillium prototype is Pencillin G Works against Staph Strep and some spirochetes Disadvantages narrow spectrum of activity and susceptibility to penicillinases o semisynthetic penicillin developed to overcome disadvantages of natural penicillin part is produced by mold part is added synthetically o penicilinase resistant penicillin pencillin that overcomes certain bacteria that are resistant to natural penicillin o extended spectrum penicillins have broader spectrum than normal pencillin effective against gram neg and gram pos but not pencillinases o penicillins B lactamase inhibitors combination of penicillin and potassium clavulanate inhibits pencillinase cephalosporins o nuclei resembles that of penicillin o 2nd 3rd 4th generation more effective against gram neg bacteria than penicillin polypeptide antibiotics o bacitracin effective against gram positives inhibits cell wall synthesis at earlier stage than penicillin used for topical application for superficial infections ie acne o vancomycin important against treatment of MRSA S Aureus caused emergence of VRE vancomycin resistant enterococci glycopeptide Antimycobacterial antibiotics o Isoniazid Works against mycobacterium tuberculosis Inhibit synthesis of mycolic acid o Ethambutol Effective only against mycobacteria Inhibits incorporation of mycolic acid into the cell wall inhibiting protein synthesis difference in ribosomal structure between prokaryotes and eukaryotes accounts for selective toxicity of antibiotics that prevent protein synthesis antibiotics that target the 70s ribosomes can have adverse effects on the cell of the host because the mitochondria has 70s ribosomes Chloramphenicol o Inhibits formation of peptide bonds in growing polypeptide chain by reacting with 50S portion of 70S prokaryotic ribosomes o Broad spectrum and inexpensive to produce o Small size allows for easy diffusion in hard to reach areas of the body Aminoglycosides aminosugars are linked by glycoside bonds o Change shape of 30S ribosome subunit in initial steps of Causes genetic code of mRNA to be read incorrectly protein synthesis o Examples of this Streptomycin Neomycin Gentamycin Alternative treatment for tuberculosis Present in nonprescription topical preparations Against Pseudomonas o Can cause hearing loss and damage to the kidneys Tetracyclines o Broad spectrum o Produced by Streptomyces o Interefere with tRNA attachment to the ribosome Macrolides presence of macrocyclic lactone ring o Erythromycin is an example o Effective against gram positive bacteria injuring the plasma membrane o Bind 50S ribosome prevents translocation Oxazolidinones MRSA o Linezolid member of antibiotic group that is used against o Effective against gram positive bacteria o Bind 50s subunit close to point where it interfaces with 30S subunit thus preventing formation of 70S subunit changes in permeability of plasma membrane which results in loss of important metabolites ie antifungal drugs Polymyxin B o Topical o Against gram negative bacteria o Combined with bacitracin and neomycin in Neosporin inhibiting nucleic acid synthesis interfere with DNA replication and transcription Rifamycin o Inhibit synthesis of RNA o Effective against tuberculosis o Can penetrate tissues and reach cerebrospinal fluid and abscesses Quinolones and Fluoroquinolones o Quinolone developed in 1960 exerts unique bactericidal effect by selectively inhibiting DNA gyrase needed for replication of DNA o Fluoroquinolone prolific group of synthetic quinolones o Ciproflaxin Against anthrax o Effective against Urinary tract infections competitive inhibitors of the synthesis of essential metabolites sulfonamides among first synthetic antimicrobial drugs used to treat microbial diseases o inhibit folic acid synthesis o have broad spectrum TESTS TO GUIDE CHEMOTHERAPY diffusion methods Kirby bauer disk diffusion test o Test strain sensitivity to multiple antibiotics by covering whole agar plate with pathogen and then placing several different antibiotics throughout the plate Zone of inhibitions cleared zones
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