Penicillin and Penicillin and Cephalosprin: Beta-Cephalosprin: Beta-

Lactam Antibiotics and Lactam Antibiotics and Other Inhibitors of Cell Other Inhibitors of Cell

Wall SynthesisWall Synthesisbyby

Dena NguyenDena Nguyen

http:www.denanguyen.tripod.http:www.denanguyen.tripod.comcom

OUTLINEOUTLINE What are antibiotics?What are antibiotics? Bactericidal vs. bacteriostaticBactericidal vs. bacteriostatic Broad spectrum vs. narrow spectrumBroad spectrum vs. narrow spectrum

What is peptidoglycan cell wall synthesisWhat is peptidoglycan cell wall synthesis Structure of peptidoglycan cell wallStructure of peptidoglycan cell wall Peptidoglycan synthesis targeting the bacterial cell wallPeptidoglycan synthesis targeting the bacterial cell wall How the drug will target the cell wall without harming usHow the drug will target the cell wall without harming us

General characteristics of Beta-Lactam General characteristics of Beta-Lactam antibioticsantibiotics

General propertiesGeneral properties Chemical structureChemical structure Mechanism of actionMechanism of action ResistanceResistance

Penicillin and Cephalosporin antibiotics Penicillin and Cephalosporin antibiotics affecting the cell wall synthesisaffecting the cell wall synthesis

Original antibiotic derivate for this familyOriginal antibiotic derivate for this family Chemical structureChemical structure Mechanism of actionMechanism of action Antibiotic spectrum of activityAntibiotic spectrum of activity

What Are Antibiotics?What Are Antibiotics?

Antibiotics:Antibiotics:-Drugs that kill or inhibit growth of -Drugs that kill or inhibit growth of microorgansimsmicroorgansims by attacking a specific targetby attacking a specific target

Bactericidal:Bactericidal:-eradicate an infection in absence of host -eradicate an infection in absence of host defense mechanismdefense mechanism

Bacteriostatic:Bacteriostatic:-inhibits microbial growth but requires host -inhibits microbial growth but requires host defense mechanisms to eradicate infectiondefense 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 How Does Synthesis of Cell Wall Peptidoglycan Occur?Wall Peptidoglycan Occur?

Peptidogylcan:Peptidogylcan:- unique to procaryotes - unique to procaryotes - provides rigid support for cell provides rigid support for cell

Composition:Composition: - murein backbone with peptide chain - murein backbone with peptide chain

- N-acetylglucosamine- N-acetylmuramuric acid - N-acetylglucosamine- N-acetylmuramuric acid (NAG-NAM)(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- 3rdrd Amino Acid is an NH2 acid 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 Antibiotics Affecting Cell Wall SynthesisSynthesis

INHIBITORS OF CELLWALL SYNTHESIS

BETA-LACTAMANTIBIOTICS

OTHER BETA-LACTAMANTIBIOTICS

PENICILLINS CEPHALOSPORINS CARBAPENEMS MONOBACTAMS

1st GENERATION

2ND GENERATION

3RD GENERATION

4TH GENERATION

CefaclorCefamandoleCefonicidCefmetazoleCefotetanCefoxitinCefuroxime

CefdinirCefiximeCefoperazoneCefotaximeCeftazidimeCeftibutenCeftizoximeCeftriazone

Cefepime

Vancomycin

AztreonamImipenem / Cilastatin*

Penicillin VKPenicillin GNafcillinOxacillinCloxacillinDicloxacillinAmpicillinAmoxicillinCarbenicillinTicarcillinPiperacillinMezlocillinAzlocillin

CefazolinCefadroxilCephalexinCephalothinCephapirinCephradine

BETA-LACTAMASEINHIBITORS

Clavulanic acidSulbactamTazobactam

General Characteristics of General Characteristics of Beta-Lactam AntibioticsBeta-Lactam Antibiotics

Chemical StructureChemical Structure:: - beta-lactam ring w/ - beta-lactam ring w/

a a neighboring ring neighboring ring

Mechanism of Mechanism of action:action:

- inhibit - inhibit transpeptidation transpeptidation

of peptidoglycan of peptidoglycan - effective on cell wall - effective on cell wall in actively growing in actively growing bacterial cells bacterial cells

Resistance:Resistance: - Beta- lactamase - Beta- lactamase

activityactivity

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

PenicillinPenicillinPrototype:Prototype:

- PCN G - 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 IM, IV, or orally - absorption of (most) oral pcns: 1) - absorption of (most) oral pcns: 1)

route of route of administration (except ex. administration (except ex. amoxicillin) amoxicillin)

2) drug-food 2) drug-food interactioninteraction

- large therapeutic range - large therapeutic range - distributed to tissues & - distributed to tissues &

renally excreted (most) renally excreted (most) - side effects are allergic - side effects are allergic

rxns / anaphalyxis rxns / anaphalyxis - cross – sensitivity to other pcns & - cross – sensitivity to other pcns &

cephalosporins cephalosporins - drug interaction w/ aminoglycosides - drug interaction w/ aminoglycosides

Spectrum:Spectrum: 1) 1) PenicillinsPenicillins (ex. PCN G)(ex. PCN G) - active w/ gram +, gram - , & non-beta-- active w/ gram +, gram - , & non-beta-lactamase producing lactamase producing

anaerobes anaerobes 2) 2) Antistaphylococcal PenicillinsAntistaphylococcal Penicillins (ex. (ex.

Nafcillin) Nafcillin) - active w/ staphylococci, streptococci- active w/ staphylococci, streptococci - inactive w/ enterococci, anaerobes, gram – - inactive w/ enterococci, anaerobes, gram – cocci & rodscocci & rods

3) 3) Extended-Spectrum PenicillinsExtended-Spectrum Penicillins (ex. (ex. Ampicillin)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.

CephalosporinsCephalosporinsProtoype:Protoype:

- - based on generationbased on generation - not a pcn derivative- not a pcn derivative

Similar to penicillins:Similar to penicillins: - - chemically chemically

Mechanism of ActionMechanism of Action - - toxicity/ therapeutic toxicity/ therapeutic - (most) excretion via - (most) excretion via

kidneys kidneys - cross- sensitivity - cross- sensitivity - adverse rxn (allergic - adverse rxn (allergic

rxn)rxn) (plus: a disulfiram-like (plus: a disulfiram-like

effect)effect)

Chemical Structure:Chemical Structure: - 7 aminocephalosporanic acid - 7 aminocephalosporanic acid - R1 & R2 important properties- R1 & R2 important properties

- stable in pH & - stable in pH & temperature temperature changes changes

- more stable to Beta-- more stable to Beta-lactamase lactamase

- (result) Broad Spectrum - (result) Broad Spectrum

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

4 Major Generations:4 Major Generations: 11stst generation : ex) cephalexin , generation : ex) cephalexin , cephadrinecephadrine

22ndnd generation : ex) cefamandole, generation : ex) cefamandole, cefaclor cefaclor

33rdrd generation : ex) ceftriaxone, generation : ex) ceftriaxone, cefixime cefixime

44thth generation : ex) cefipime generation : ex) cefipime

ReferenceReference www.mednet.odessa.ua/med/pharm/blactams.htwww.mednet.odessa.ua/med/pharm/blactams.ht

mm..

http://sprojects.mmimcgill.ca/antibiotic/bcwi.htmhttp://sprojects.mmimcgill.ca/antibiotic/bcwi.htm..

www.worldhistory.com/wiki/B/Beta-lactam-antibiwww.worldhistory.com/wiki/B/Beta-lactam-antibiotic.htmotic.htm..

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

www.surfablebooks.com/wbmedical/32447/32531www.surfablebooks.com/wbmedical/32447/32531/2.htm/2.htm..

www.cs.stedwards.edu/chem/Chemistry/CHEM4www.cs.stedwards.edu/chem/Chemistry/CHEM43/CHEM43/Antibiotics/Antibiotics.html3/CHEM43/Antibiotics/Antibiotics.html..