Antibacterial Antibiotics (Part 1) PDF

ANTIBACTERIAL ANTIBIOTICS Topic Outline 1. Introduction 2. Review of Bacteria 3. Mechanisms of Antibacterial Action 4. Specific Antibacterial Antibiotics Introduction ANTIBACTERIAL ANTIBIOTICS HISTORICAL OVERVIEW: Molded curd of soybean to treat boils and carbuncles (in Chinese fol...

ANTIBACTERIAL ANTIBIOTICS Topic Outline 1. Introduction 2. Review of Bacteria 3. Mechanisms of Antibacterial Action 4. Specific Antibacterial Antibiotics Introduction ANTIBACTERIAL ANTIBIOTICS HISTORICAL OVERVIEW: Molded curd of soybean to treat boils and carbuncles (in Chinese folk medicine) 1877 – Pasteur and Joubert Anthrax bacilli were killed when grown in culture in the presence of certain bacteria. Vuilllemin’s concept of ANTIBIOSIS ANTIBACTERIAL ANTIBIOTICS HISTORICAL OVERVIEW: Arsenic phils 1909 – Ehrlich’s discovery of Arsphenamine 1929 - Fleming’s discovery of penicillin psulfonamides 1935 – Domagk’s discovery of sulfa drugs 1938 - Florey and Chain introduced penicillin in therapy ↳ they purify and did mass I freeze drying method of purification antimicrobial - synthetic antibiotic and natural a protocol for - natural production ANTIBACTERIAL ANTIBIOTICS HISTORICAL OVERVIEW: Waksman defined “An antibiotic or antibiotic substance is a substance produced by microorganisms, which has the capacity of inhibiting the growth and even of destroying other microorganisms.” ANTIBACTERIAL ANTIBIOTICS HISTORICAL OVERVIEW: Expanded Definition of Antibiotics: 1. It is a product of metabolism (although it may be duplicated or even have been anticipated by chemical synthesis). 2. It is a synthetic product produced as a structural analog of a naturally occurring antibiotic. ANTIBACTERIAL ANTIBIOTICS HISTORICAL OVERVIEW: 3. It antagonizes the growth or survival of one or more species of microorganisms. 4. It is effective in low concentrations.  ANTIBACTERIAL ANTIBIOTICS molecular ducking ? An Ideal Antibiotic § Selectively toxic ↳ magic bullet § Chemically stable § Rate of elimination is _____ SLOW enough for dosing schedule, but rapid and complete enough for removal  ANTIBACTERIAL ANTIBIOTICS Commercial Production 1) Preparation of pure culture 2) Fermentation 3) Isolation - 4) Purification - 5) Assays - 6) Formulation - Review of Bacteria  Differences between Bacterial and Animal Cells: oa rgion sa open space or & region prucliod the bacterial cell does not have a defined nucleus, whereas the animal cell does; animal cells contain a variety of structures called organelles, whereas the bacterial cell is relatively simple; Differences between Bacterial and Animal Cells: the biochemistry of a bacterial cell differs significantly from that of an Ribosome Microbe Animals animal cell; and 60s 50s + 40s +30 80s · it condenses + the bacterial cell has a cell membrane 70S 60s + 40s 80s and a cell wall, whereas the animal cell D has only a cell membrane. Mechanisms of Antibacterial Action ANTIBACTERIAL ANTIBIOTICS MECHANISM OF ACTION The MOA of antibiotics varies. Understanding the MOA is the basis for future development of antibacterial antibiotics. ANTIBACTERIAL ANTIBIOTICS MECHANISM OF ACTION Antimicrobial drugs can be either bacterio_____ static (inhibit growth) or bacteri_____ cidal (kill).  ANTIBACTERIAL ANTIBIOTICS MECHANISM OF ACTION 1. Inhibition of cell wall synthesis 2. · Interactions withProquinolthe RNA plasma membrane ⑤ DNA ones rifampicin 3. Inhibition of nucleic acid synthesis =. - 4. Disruption of protein synthesis ↳ 5. Inhibition of cell metabolism Specifc Antibacterial Agents TDS MQ R BVB PokeDapo He CLEC El ANTIBACTERIAL ANTIBIOTICS CHEMICAL CLASSIFICATION - Penicillins, cephalosporins (B-lactam ring) - Tetracyclines (4-annulated rings) - Aminoglycosides (amino sugars) - Macrolides (large lactone ring) - Bacitracins, polymyxins (polypeptides) - Special Topic: Newer Agents  lactam Beta Ring  like tetracycline napkin (4 rings) macrolides aminoglycosides  ANTIBACTERIAL ANTIBIOTICS Inhibitors of a gonduct -blockme Cell Wall Synthesis bridge dock rate a with 4 types 1. B-lactam antibiotics n9 antibiotics" that has a group of structure their - to similarity which is the beta-lactam ring - Penicillins common is the sing beta-lactam the ring-differ in - Cephalosporins adjacent ring - Monobactams amide - Carbapenems ANTIBACTERIAL ANTIBIOTICS plant opeptidoglycan layer cellulose - - chitin-fungi THE BACTERIAL CELL WALL Absent from mammalian cells * Potential for selective chemotherapy Functions: 1) Semipermeable barrier from substances 2) Barrier from osmotic pressure changes 3) Prevent digestion by host enzymes  I ↳ Be+a 1 4 - Glycosidic Bonds - Lalanineseage NAM Nacetylmuranic acid N-acetyl glucosamine to the -nearest originally A chain peptide Intamic penta 5th is D-alanine D to complete 2nd in order layer - the peptidoglycan to bebroken it needs 4 cross bridges (6t) L-lysine acid (6) Diaminopimelic 3rd - D-alanine - farthest The beta-lactam blocks the enzyme that "hagpaphtol" ng penta-tetra i needs ↳ to complete The peptidoglycan · The beta-lactam blocks the enzyme the that synthesizes cross bridges thick  Gram() -D pyrogen-causes fever bacteria when ↳ endotoxin -> structure of dead this will part of - bacteria be separated the thin Gram (t) ANTIBACTERIAL ANTIBIOTICS BETA-LACTAM ANTIBIOTICS - § Possess B-lactam ring (4-membered-cyclic amide) § Penicillin G (benzylpenicillin) and Penicillin V (phenoxy methylpenicillin) - agents of choice ANTIBACTERIAL ANTIBIOTICS BETA-LACTAM ANTIBIOTICS § Potent, rapid bactericidal action § Low toxicity § Inhibits synthesis of PEPTIDOGLYCAN – provides strength and rigidity to the cell wall responsible for 1) D-TRANSPEPTIDASE - cross bridge 2) D-ALANINE CARBOXYLPEPTIDASE ↳ hydrolyze D-ala-D-ala bonds - d-alahine  ANTIBACTERIAL ANTIBIOTICS Beta-lactams exerts effect by blocking the enzymes Penicillin-Binding Proteins (PBPs) § PBPs 1a and 1b - cell elongation Inh à spheroplast formation à cell lysis § PBP 2 - maintains rod shape of bacilli Inh à ovoid/round forms à delayed lysis  ANTIBACTERIAL ANTIBIOTICS Penicillin-Binding Proteins (PBPs) § PBP 3 - septum formation Inh à filamentous form àcannot separate § PBP 4 to 6 - carboxylpeptidase Inh à NOT lethal to bacterium  ANTIBACTERIAL ANTIBIOTICS Penicillin-Binding Proteins (PBPs) § Penicillin G à _______ PBP 3 § PBP ta 1st Gen Cephalosporins à ______ § Amdinocillin àPBP 2 § Others à PBPs 1, 2, 3 THE PENICILLINS ANTIBACTERIAL ANTIBIOTICS THE PENICILLINS § Commercial production from _________________________ penicillium Chrysogenum § Core nucleus PHARMACOPHORE-a true an effect à 6-aminopenicillanic acid (6-APA) # specific part responsible for the § Fermentation-derived: drug the effect of Pen G, Pen V and 6-APA § Sodium and potassium salts are crystalline, hydroscopic and water soluble. STRUCTURE OF PENICILLIN - Deni SAR of are R · mostly and can change beneficial = sulfone acid-stability amino penicillanic ring beneficial and can change I. Lbeta ANTIBACTERIAL ANTIBIOTICS Nomenclature § CAS: - Sulfur atom (1); Nitrogen atom (4) - definitive but too complex - 6-acylamino-2,2,- dimethyl-3-carboxylic acid ANTIBACTERIAL ANTIBIOTICS Nomenclature § USP: - Nitrogen atom (1); Sulfur atom (4) - 4-thia-1- azabicycloheptone ANTIBACTERIAL ANTIBIOTICS EXAMPLE (CAS): BENZYLPENICILLIN SODIUM § monosodium (2S,5R,6R)-3,3-dimethyl- 7-oxo)-6-(2-phenylacetamido)-4-thia- l-azabicyclo[3.2.0]heptane-2- carboxylate  ANTIBACTERIAL ANTIBIOTICS SIMPLIFIED FORMS OF NOMENCLATURE: 1. “penam” – bicyclic system w/o substituents 2. “penicillanic acid” – ring w/ substituents 3. “penicillin” + R-chain  ANTIBACTERIAL ANTIBIOTICS Stereochemistry USP § Three chiral centers § USP: C2, C5, C6 Biosynthesis of Penicillins § 6-APA derived from two amino acids: L- cysteine and L-valine  ANTIBACTERIAL ANTIBIOTICS Chemical Instabilities § Most penicillins are ACIDS. § Na and K salts – highly water-soluble § Benzathine, procaine – poorly water soluble (depot forms for longer duration) § Hygroscopic  ANTIBACTERIAL ANTIBIOTICS Chemical Degradation § HYDROLYSIS – main cause of deterioration § B-lactam amide bond – most unstable bond  read * kindly Weakly acidic, basic, PENICILLIN nucleophile (water) Strongly acidic pH