Penicillin and Cephalosprin: Beta- Lactam Antibiotics and Other Inhibitors of Cell Wall Synthesis by Dena Nguyen

OUTLINE What are antibiotics? What are antibiotics? Bactericidal vs. bacteriostatic Bactericidal vs. bacteriostatic Broad spectrum vs. narrow spectrum Broad spectrum vs. narrow spectrum What is peptidoglycan cell wall synthesis What is peptidoglycan cell wall synthesis Structure of peptidoglycan cell wall Structure of peptidoglycan cell wall Peptidoglycan synthesis targeting the bacterial cell wall Peptidoglycan synthesis targeting the bacterial cell wall How the drug will target the cell wall without harming us How the drug will target the cell wall without harming us General characteristics of Beta-Lactam antibiotics General characteristics of Beta-Lactam antibiotics General properties General properties Chemical structure Chemical structure Mechanism of action Mechanism of action Resistance Resistance Penicillin and Cephalosporin antibiotics affecting the cell wall synthesis Penicillin and Cephalosporin antibiotics affecting the cell wall synthesis Original antibiotic derivate for this family Original antibiotic derivate for this family Chemical structure Chemical structure Mechanism of action Mechanism of action Antibiotic spectrum of activity Antibiotic spectrum of activity

What Are Antibiotics? Antibiotics: Antibiotics: -Drugs that kill or inhibit growth of microorgansims by attacking a specific target by attacking a specific target Bactericidal: Bactericidal: -eradicate an infection in absence of host defense mechanism Bacteriostatic: Bacteriostatic: -inhibits microbial growth but requires host defense mechanisms to eradicate infection

Narrow Spectrum -Specific for a small range of microorganisms Broad Spectrum -Effective against a wide range of microorganisms Selective Toxicity -More toxic to the invader than to the host -a property of useful antimicrobial drugs -for example: cell wall, ribosome, nucleus, and cell membrane

How Does Synthesis of Cell Wall Peptidoglycan Occur? Peptidogylcan: - unique to procaryotes - provides rigid support for cell Composition: - murein backbone with peptide chain - murein backbone with peptide chain - N-acetylglucosamine- N-acetylmuramuric acid (NAG-NAM) - N-acetylglucosamine- N-acetylmuramuric acid (NAG-NAM) - pentapeptide with L & D amino acids - pentapeptide with L & D amino acids Peptidoglycan Synthesis: Peptidoglycan Synthesis: - 4 main steps - 4 main steps - 3 rd Amino Acid is an NH2 acid - 3 rd Amino Acid is an NH2 acid (lysine = gram + / diaminopimelic acid = gram -) (lysine = gram + / diaminopimelic acid = gram -) - catalyzed by PBPs - catalyzed by PBPs - (D-Ala-D-ala) - (D-Ala-D-ala)

Katzung, B. (2003): Basic and Clinical Pharmacology; McGraw-Hill, 9th edition. Katzung, B. (2003): Basic and Clinical Pharmacology; McGraw-Hill, 9th edition.

Antibiotics Affecting Cell Wall Synthesis BETA-LACTAMASE INHIBITORS   Clavulanic acid   Sulbactam   Tazobactam

General Characteristics of Beta- Lactam Antibiotics Chemical Structure : - beta-lactam ring w/ a - beta-lactam ring w/ a neighboring ring neighboring ring Mechanism of action: - inhibit transpeptidation - inhibit transpeptidation of peptidoglycan of peptidoglycan - effective on cell wall - effective on cell wall in actively growing in actively growing bacterial cells bacterial cellsResistance: - Beta- lactamase activity - Beta- lactamase activity Katzung, B. (2003): Basic and Clinical Pharmacology; McGraw-Hill, 9th edition. Katzung, B. (2003): Basic and Clinical Pharmacology; McGraw-Hill, 9th edition.

Penicillin Prototype: - PCN G Chemical Structure: Chemical Structure: - 6-aminoepnicillanoic acid - 6-aminoepnicillanoic acid Mechanism of action: Mechanism of action: - binds to PBP - binds to PBP Properties: Properties: - IM, IV, or orally - absorption of (most) oral pcns: 1) route of administration (except ex. amoxicillin) 2) drug-food interaction 2) drug-food interaction - large therapeutic range - large therapeutic range - distributed to tissues & renally excreted (most) - distributed to tissues & renally excreted (most) - side effects are allergic rxns / anaphalyxis - side effects are allergic rxns / anaphalyxis - cross – sensitivity to other pcns & cephalosporins - cross – sensitivity to other pcns & cephalosporins - drug interaction w/ aminoglycosides

Spectrum: 1) Penicillins (ex. PCN G) - active w/ gram +, gram -, & non-beta-lactamase producing - active w/ gram +, gram -, & non-beta-lactamase producing anaerobes anaerobes 2) Antistaphylococcal Penicillins (ex. Nafcillin) 2) Antistaphylococcal Penicillins (ex. Nafcillin) - active w/ staphylococci, streptococci - active w/ staphylococci, streptococci - inactive w/ enterococci, anaerobes, gram – cocci & rods - inactive w/ enterococci, anaerobes, gram – cocci & rods 3) Extended-Spectrum Penicillins (ex. Ampicillin) 3) Extended-Spectrum Penicillins (ex. Ampicillin) - active w/ most gram – - active w/ most gram – Katzung, B. (2003): Basic and Clinical Pharmacology; McGraw-Hill, 9th edition. Katzung, B. (2003): Basic and Clinical Pharmacology; McGraw-Hill, 9th edition.

CephalosporinsProtoype: - based on generation - based on generation - not a pcn derivative - not a pcn derivative Similar to penicillins: Similar to penicillins: - chemically - chemically Mechanism of Action Mechanism of Action - toxicity/ therapeutic - toxicity/ therapeutic - (most) excretion via kidneys - (most) excretion via kidneys - cross- sensitivity - cross- sensitivity - adverse rxn (allergic rxn) - adverse rxn (allergic rxn) (plus: a disulfiram-like effect) (plus: a disulfiram-like effect) Chemical Structure: Chemical Structure: - 7 aminocephalosporanic acid - 7 aminocephalosporanic acid - R1 & R2 important properties - R1 & R2 important properties - stable in pH & temperature changes - stable in pH & temperature changes - more stable to Beta-lactamase - more stable to Beta-lactamase - (result) Broad Spectrum - (result) Broad Spectrum Katzung, B. (2003): Basic and Clinical Pharmacology; McGraw-Hill, 9th edition. Katzung, B. (2003): Basic and Clinical Pharmacology; McGraw-Hill, 9th edition.

4 Major Generations: 1 st generation : ex) cephalexin, cephadrine 1 st generation : ex) cephalexin, cephadrine 2 nd generation : ex) cefamandole, cefaclor 2 nd generation : ex) cefamandole, cefaclor 3 rd generation : ex) ceftriaxone, cefixime 3 rd generation : ex) ceftriaxone, cefixime 4 th generation : ex) cefipime 4 th generation : ex) cefipime

Reference Katzung, B. (2003): Basic and Clinical Pharmacology; McGraw- Hill, 9 th edition. Katzung, B. (2003): Basic and Clinical Pharmacology; McGraw- Hill, 9 th edition Antibiotics/Antibiotics.html. Antibiotics/Antibiotics.html. Antibiotics/Antibiotics.html Antibiotics/Antibiotics.html