CHAPTER 21: BACTERIAPaul Ehrlich- German physician and bacteriologist - Observed that some cells dye stained some cells but not other indicating a fundamental difference in the cell membranes o Helps spark the idea that some bacteria would kill some cells and not others- Discovered the cure for syphilis by researching effective arsenic compounds- This drug was Salvarsano Toxin, termed the magic bullet, but killed Terponema HISTORY AND DEVELOPMENT - Discovery of Antimicrobial Drugso Ehrlich discovered the first antimicrobial with Salvarsano Domagk discovered a red dye that was affective against strep infections in animals It only is affective with the blood enzyme split the Prontosil molecule into sulfanilamide, which acted against the infection Termed the sulfa drugo Chemotheraputic agent: any chemical that combats a diseaseo Antimicrobial drug: treat a microbial infection- Discovery of antibioticso Alexander Fleming, while observing staph that was being inhibited by a mold species: Penicillium In his lifetime, he proved the effectiveness but was never able to purify penicillino Ernst Chain and Howard Florey purified penicillin 10 years later  Put in affect large scale operation by being able to study the structure of the drug Used in large scale in the war  Penicillin G was found to be the most effective  First antibiotico Selman Waksman  Discovered strepomysin by isolating bacteria in soil- Development of New Generation Drugso Concern of super drugs via overuse and pathogen adaptabilityo Scientists are able to change the properties of one microbial agent  Ex: penicillin g into ampicillin FEATURES OF ANTIMICROBIAL DRUGS- Commercial Productiono Can come from the lab, soil, bacteria and fungio Semi-synthetic: when the drug is chemically altered after beinggrown and isolated in the labo Grow strain in broth medium in fermentation tanko Incubate to maximum antibiotic concentrationo Extract drug from mediumo Purify drug (them chemically modifed) - Selective toxicityo Meaning causing greater harm to the microbe than to the body o Interfere with essential biological processes of themicroorganism, but not the hosto Expressed in a therapeutic index: the lowest toxic does to thepatient divided by the dose used for therapy  When an agent has a high therapeutic index, like penicillin, a large amount can be administered without fear of toxins in the blood becoming high Bactracin, pencillin (beta lactams), vancomysin- Antimicrobial Actiono Bacteriostatic: inhibit growth of organisms, but when removed growth can/will resumeo Bacteriocidal: sterilizing and fully kill microbial life- Spectrum of Activity o Broad-spectrum antibiotics: ones that kill a wide range of species Can disrupt the normal flora in the body o Narrow spectrum: target a small number of species Kills less of the normal flora in the body - Effects of Combinations of Antimicrobial Drugso Some drugs when used in combo with each other have neg effects Bacteriostatic agents limit the effects of drugs that kill rapidly dividing cells o Antagonistic: when one drug has a negative effect on the performance of another o Synergistic: one drug enhances the ability of another o Additive: drugs that are neutral and have no effect on the other- Tissue Distribution, Metabolism, and Excretion of the Drugo Drugs have different characteristics that impede effectiveness  If they can pass through CSF or whether or not they are able to be stable at pHo Half-life: the amount of time needed to eliminate ½ of the drug from the body  Depends on size and frequency of the dosage- Adverse Effectso Allergic Reactions Can result in fever, rash or anaphylactic shocko Toxic Efects Aplastic anemia: a condition caused by toxic levels of chloramphenicol in which the body cannot make RBCs and WBCso Suppression of the Normal Microbiota Antibiotic associated colitis: caused by the growth of toxin producing C. Difficilie This is normal flora, but when other flora is suppressed, this bacteria will become dominant in the culture and cause illnesso Resistance to Antimicrobials Innate, intrinstic, resistance: when bacteria is inherently resistant to certain drug effects Acquired resistance: when new genes create the resistanceMechanisms of Action of Antibacterial Drugs- Beta lactam drugs that inhibit cell wall synthesis Inhibit synthesis by makeing prokaryotic ribosomes targets Have a b-lactam ring Inhibit PBP pencillin binding proteins (enzymes) Each class of drug binds to a particular position on the ribosomes to block translation Bacteriocidal and inhibits cell wall synthesis Vary in spectrum against Gram + and – Resistance is due to the synthesis of B-lactamanses (enzyme that breaks the beta lactam ring)o Natural Penicillins Narrow spectrum Work against Gram + and come gram –o Penicillinase-resistance penicillin Side chains prevent inactivation from penicillinaseso Broad-spectrum Modified side chains for broad spectrumo Extended spectrum Better against Pseudomonaso Penicillins and beta lactamase inhibitor Combination penicillin drug = enzyme inhibitor Augmentin = amoxicillin + clavulanic acido Cephalosporin Structures resistant to inactivation from b-lactamnases Chemically modified to produce several generations of related cephlosporins Cefactor, cephalexin… Gram negative bacteriao Vancomycin Blocks PG peptide chains  Used against penicillinR Gram + bercause cannot cross gram negative outer membrane By IV onlypoor absorption from GI tract Levels needto be monitored in blood VanR: most by alterations in the sidechain of the NAM molecule- Protein Synthesis Inhibitorso Macroslides Erythromyosin, clarithromycin, azithromysin Reversibly bind to the 50S ribome Effective against cariety of gram + and mycobacterium Resistance via:- Modification of rRNA target- Production of enzyme that modifies drug - Inhibition of nucleic acid sythesiso Rifamycins Block bacterial RNA polymerase and therefore transcription Anti-Gr+ Primarily used to treat TB and leprosy and meningitis  Resistance is due to a mutation in the RNA polymerase geneo Fluoroquinolones Ciprofloxacin Inhibittopoisomerase DNA gyrase which is responsible for DNA supercoiling Effective against Gram positive and Gram negative bacteria Resistance due to alteration of DNA gyrase - Inhibtion of metabolic pathwayso Relatively few drugso Most