Microbiology -Chapter 9 Antibiotics
Microbiology -Chapter 9 Antibiotics BSC 302
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This 5 page Class Notes was uploaded by Sydney Coll on Friday October 14, 2016. The Class Notes belongs to BSC 302 at Marshall University taught by Dr. Mosher in Fall 2016. Since its upload, it has received 20 views. For similar materials see Microbiology in Biology at Marshall University.
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Date Created: 10/14/16
Chapter 9 – Antibiotics Golden Age of Antibiotics Antibiotics: compounds produced by one microbe that adversely affect other microbes Modern antibiotic revolution began in 1928 with discovery of penicillin by Alexander Fleming o Contaminating mold had inhibited growth of Staph aureus colonies on a plate Penicillin was purified by Florey and Chain Domagk – discovered sulfa drugs o Inactive until converted by body to active agents o Analogs of PABA Waksman – discovered streptomycin Fundamentals of Antimicrobial Therapy Antibiotics comprise the vast majority of chemotherapeutic agents used to treat microbial disease Antibiotic – synthetic chemotherapeutic agent that is clinically useful and chemically synthesized Selective Toxicity Antibiotics must affect the target organism, but it must not affect humans Many antibiotics have side effects at high concentrations o Chloramphenicol interferes with ribosomes o Some cause allergies Drug should affect microbial physiology Does not exist in humans o Peptidoglycan o Differences in ribosomal structure o Biochemical pathways missing Limited Spectrum of Activity Broad spectrum: effective against many species Narrow spectrum: effective against few or a single species Source of antibiotics: o Most as natural products o Often modified by artificial means to increase efficacy and decrease toxicity to humans Bacteriostatic vs. Bactericidal Bactericidal: antibiotics that kill the target organism o Many drugs only affect the growing cells o Inhibitor of cell wall synthesis – only effective if organism is building new cell wall (penicillin) Bacteriostatic: prevent the growth of organism o Cannot kill the organism o Immune system removes intruding microbe Drug Susceptibility Must consider: o Relative effectiveness o Average attainable tissue level of the drugs Minimal Inhibitory Concentration MIC: the lowest concentration that prevents growth o Tested by diluting antibiotics Lowest concentration with no growth = MIC May still have living, but non-growing, organisms Plate liquid without antibiotics and see if colonies form o No colonies = minimal lethal concentration )MLC) o MLC always lower than MIC Strip tests avoid need for dilutions MIC is the point at which the elliptical zone of inhibition intersects with the strip Kirby-Bauer Disk Susceptibility Test Kirby-Bauer Assay test strain sensitivity to antibiotics Uses series of round filter paper disks impregnated with different antibiotics Dispense delivers up to 12 disks to surface of agar plate Drugs diffuse away from disks into surrounding agar and inhibit growth of bacteria o Size of cleared zone represents relative sensitivity Mechanisms of Action Targets: o Cell wall and membrane o DNA, RNA, and protein synthesis o Metabolism Cell Wall Antibiotics Peptidoglycan synthesis: o Precursor made in cytoplasm o Carried across membrane by lipid carrier (bactoprenol) o Precursors are polymerized to existing cell wall structure (transglycosylase) o Peptide side chains are cross-linked (transpeptidase) Beta-Lactam antibiotics: o Penicillin o Allows drug to bind transpeptidase and transglycosylase, preventing activities and stopping synthesis of chain Vancomycin: binds ends of peptides and prevents action of transglycosylase and transpeptidase Cycloserine: inhibits formation of dipeptide precursor Bacitracin: blocks lipid carrier Cell Membrane Inhibitors Gramicidn: forms cation channel through which ions leak Polymyxin: destroys cell membrane (used topically) DNA Synthesis Inhibitors Quinolones: block bacterial DNA gyrase and prevent DNA replication o Nalidixic acid Metronizadole: nontoxic, unless metabolized by anaerobe ferredoxin Sulfa Drugs: needed for DNA synthesis RNA Synthesis Inhibitors Antibiotics that inhibit transcription are bactericidal and most active against growing bacteria Rifampin: o Binds to beta subunit of RNA polymerase o Prevents elongation step of transcription **Actinomycin D: o Prevents initiation step of transcription o Binds to DNA from any source Not selectively toxic, can also affect eukaryotic cells Protein Synthesis Inhibitors Drugs that affect 30S subunit: o Tetracycline: block binding of charged tRNAs to the A site of ribosome – proteins cannot be made or synthesized Bacteriostatic – stop growth, do not kill Drugs that affect 50S subunit: o Macrolides: inhibit translocation o Chloramphenicol: inhibits peptidyl transferase activity Challenges of Drug Resistance Antibiotics are considered secondary metabolites because they usually don’t have apparent primary uses in producing organisms o Not essential for survival o Enhance ability to survive competition Microbes prevent self-destruction by means of various antibiotic resistance mechanisms o Make enzymes to disable antibiotics o Genes encode some drug-resistance mechanisms that have been transferred to pathogens Forms of Antibiotic Resistance 1. Alter the target o Modify the ribosomal proteins confers resistance to streptomycin 2. Degrade the antibiotic o Beta-lactamase enzyme destroys penicillin o One of most common types 3. Modify the antibiotic o Add modifying groups that inactive antibiotic 4. Pump antibiotic cell out of cell o Specific and nonspecific transport proteins o Similar strategy used in cancer cells How Resistance Develops De novo antibiotic resistance develops through gene duplication and/or mutations Can be acquired via horizontal gene transfer (plasmids) o Conjugation o Transduction o Transformation Integrons Fighting Drug Resistance Dummy target compounds that inactive resistant enzymes Alter antibiotic’s structure so that it sterically hinders access of modifying enzymes Link antibiotics together Future of Drug Discovery Evolutionary pressure is constant – requires constant search for new antibiotics Modern drug discovery process: o Identify new targets using genomics o Determine spectrum of compound – broad or narrow o Determine pharmaceutical properties – not toxic to animals New therapies: o Nanotubes to poke holes in cell membranes o Molecules that cork type III section apparatus o Interfering with quorum-sensing mechanisms Antiviral Agents o Common cold – rhinovirus o No antibiotic designed for bacteria can touch rhinovirus o Applying principle of selective toxicity is harder for viruses than for bacteria o Viruses usurp host cell functions to make copies of themselves o Few targets unique to virus o Preventing virus uncoating or releasing: o Influenza (enveloped) is vulnerable Amantadine inhibits viral uncoating – prevents entry into host cell o DNA synthesis inhbitors: o Most antiviral agents inhibit viral DNA synthesis o Inserted into growing viral DNA strand, and this inhibit new DNA synthesis Antiretroviral Therapy Reverse transcriptase inhibitors: unique to retroviruses Protease inhibitors: blocks protease (making of mature proteins) – HIV Entry inhibitors: prevents binding to receptor Antifungal Agents Fungal infections more difficult to treat that bacterial infections o Fungi are selectively toxic because they are eukaryotes o Fungi have efficient drug detoxification system Divided into 2 main groups: o Superficial mycoses – topical treatment o Deep mycoses – treated systematically Azoles: inhibits synthesis of membrane sterols o Synthetic drugs o Chlotrimzaole, intraconzole, fluconazole Terbinafine: selectively inhibit ergosterol synthesis o Synthetic o Lamisil
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