Penicillin

KRVS Chaitanya

Bacterial Cell structure

Gram positive vs. Gram negative bacteria

Source: Google Images

Cell Wall

Source: Google Images

Structure of Peptidoglycan layer

•Peptidoglycan is a carbohydrate composed of alternating units of NAMA and NAGA.

•The NAMA units have a peptide side chain which can be cross linked from the L-Lys residue to the terminal D-Ala-D-Ala link on a neighboring NAMA unit.

Source: Google Images

Transpeptidase Enzyme

•The cross linking reaction is catalyzed by a class of transpeptidases known as penicillin binding proteins

•A critical part of the process is the recognition of the D-Ala-D-Ala sequence of the NAMA peptide side chain by the PBP. Interfering with this recognition disrupts the cell wall synthesis.

•β-lactams mimic the structure of the D-Ala-D-Ala link and bind to the active site of PBPs, disrupting the cross-linking process.

Source: Google Images

Beta–lactam Drugs

Beta-Lactam Antibiotics

β-lactam ring

•Contains a beta-lactam ring in their molecular structures.

•Nitrogen is attached to the beta carbon relative to the carbonyl ring and hence the name.

Classification

•Penicillins

•Cephalosporins

•Other β-Lactam drugs

--Cephamycins--Carbapenems--Oxacephalosporins --β-Lactamase inhibitors--Monolactams

Semisynthetic Penicillins

1.Acid resistant alternative to PnG Penicillin V (phenoxymethy peniciillin) 2. Penicillinase resistant penicillins methicillin and cloxacillin 3.Extended specturm penicillins A)Aminopenicillins: ampicillin, bacampicillin, amoxicillin B)Carboxypenicillins: carbenicillin, ticarcillin C)Ureidopeniciilins: pipercillin and mezlocillin4. Beta lactamase inhibitors Clavulanic acid, sulbactam and tazobactam

Beta-Lactam Structure

Discovery of Penicillin(First beta-lactam drug)

•Discovered in 1928.

• While working in his lab, trying to kill a deadly bacteria,he noticed a

blue mold growing on the dish

•Learned that it was the mold Penicillum Notatum.

•Penicillin is found in this mold.

•Noticed that the bacteria around the mold was dissolving.Source: Google Images

How it is was Developed

• For 9 years, nobody could purify the Penicillum Notatum to get the pure penicillin.

Finally, in 1938, a team of Oxford University Scientists, headed by Howard Florey and Ernst B. Chain helped to develop penicillin.

Source: Google Images

Penicillin

Natural Penicillin

How do they work?

1. The β-lactam binds to Penicillin Binding Protein (PBP)

2. PBP is unable to crosslink peptidoglycan chains

3. The bacteria is unable to synthesize a stable cell wall

4. The bacteria is lysed

• Narrow spectrum• Steptococci, staph. Aureus, niesseria gonoarrhoeae,

n.meningitiidis, B anthracis, corynebacterium diphtheriiae, clostridia, actinomyces israeli are sensitive to PnG

• Mycobacteriuim tuvberculosis, chlamydeiase,rickettsiae, protozoa, fungi and viruses are totally insensitive to PnG

• Rapid absorption and complete, peak plasma level in 30 min,• Reach most body fluids except CSF• 60% Protein bound, little metabolized because of rapid

excretion mainly glomerular filteration and secretion • Tubular secretion can be blocked by using probenecid.

PENICILLIN G

USES

• Streptococcal infections• Penumococcal infections• Meningococcal infections• Gonorrhoea• Syphilis • Dyptheria• Tetanus and gas gangrene• Drug of choice for rare

diseases like anthrax, actinomycetes, trench mouth, rat bite fever and those caused by listeria monocyotogenes

Prophylactic uses

• Rheumatic fever• Bacteria endocarditis• Agranulocytosis patients

Adverse effects of penicillin G

• PnG is one of the most nontoxic antibiotic up to 20 MU has been injected in a day without any organ toxicity

• Pain at i.m injection site,• Nauseas on oral ingestion • Thrombophlebitis of injected vein• Mental confusion• Muscular wasting/ twitching• Convulsion and coma

• Bleeding.• Arachnoiditis and degenerative changes in spinal cord.• Hallucinations and convulsion .• hypersensitivity• Allergy• Rashes, itching, urticarial and fever• Wheezing, angioneurotic edema, serum sickness • Exofoliative dermatitis• Anaphylaxis is rare

Adverse effects of penicillin G

Preparation of penicillin G

• Sod.penicillin G (crystalline penicillin) –i.m/i.v• Repository penicillin G injections: insoluble

salts of PnG,Must be deep i.mThey release slowly at the site of injection

e.g: Procaine penicillin G (Inj) Benzathine penicillin G (Inj)

Penicillin V (Phenoxymethylpenicillin)

EFFECTIVE AGAINST:• Gram positive + Less effective

against Gram negative bacteriaTREATMENT FOR:• Tonsillitis• Anthrax • Rheumatic fever • Streptococcal skin infectionsCHARACTERISTICS:• Narrow spectrum• Should be given orally• Prone to beta-lactamase

Amino-Penicillin

NO

HN

SMe

Me

COOH

CC

R

O

NH2H

Ampicillin R=Ph

Amoxicillin R= Ph-OH

AmpicillinEFFECTIVE AGAINST:• Gram positive + Gram negative

bacteriaTREATMENT FOR:• Ear infection• Sinusitis• Urinary tract infections• MeningitisCHARACTERISTICS:• Broad spectrum• Can be given orally and

parenterally• Prone to beta-lactamase

Ampicillin

Sulbactam

+

llUnasyn

AmoxicillinEFFECTIVE AGAINST:• Gram positive + Gram negative bacteriaTREATMENT FOR:• Skin infection• Sinusitis• Urinary tract infections• Streptococcal pharyngitisCHARACTERISTICS:• Broad spectrum• Can be given orally and parenterally• Prone to beta-lactamase SIDE-EFFECTS:• Rash, diarrhea, vomiting, nausea,

edema, stomatitis, and easy fatigue.

Amoxicillin

Clavulanic Acid

+

llAugmentin

Anti-Staphylococcal Penicillin

NO

NHS

Me

Me

COOH

O

MethicillinEFFECTIVE AGAINST:• Gram positive bacteriaTREATMENT FOR:Nosocomial infectionCHARACTERISTICS:• Very narrow Spectrum• Should be given parenterallySIDE-EFFECT:• Interstitial nephritis

OxacillinEFFECTIVE AGAINST:• Gram positive bacteriaTREATMENT AGAINST:• penicillin-resistant Staphylococcus

aureusCHARACTERISTICS:• Very narrow Spectrum• Should be given parenterallySIDE-EFFECT:• Hypersensitivity and local reactions• In high doses, renal, hepatic, or

nervous system effects can occur

FlucloxacillinEFFECTIVE AGAINST:• Gram positive bacteria +

Staphylococci that produce beta-lactamase

CHARACTERISTICS:• Very narrow Spectrum• Should be given orallySIDE-EFFECT:• Allergic reaction• Diarrhoea, nausea, rash, urticaria

pain and inflammation at injection site

Anti-Pseudomonal Penicillin

PiperacillinEFFECTIVE AGAINST:• Gram positive +Gram negativeCHARACTERISTICS:• Extended Spectrum• Should be given

by intravenous or intramuscular injectionSIDE-EFFECT:• Hypersensitivity• Gastrointestinal• Renal• Nervous system

*Piperacillin+Tazobactam=Zosyn

CarbenicillinEFFECTIVE AGAINST:• Gram negative + Limited Gram

positiveTREATMENT FOR:• Urinary tract infectionsCHARACTERISTICS:• Highly soluble in water and acid-

labileSIDE-EFFECT:• High doses can cause bleeding• Hypokalemia

BETA-LACTAMASE INHIBITORS

• Resemble β-lactam antibiotic structure • Bind to β-lactamase and protect the antibiotic from destruction• Most successful when they bind the β-lactamase irreversibly • Three important in medicine:

» Clavulanic Acid» Sulbactam» Tazobactam

Beta–lactam Resistance

Resistance-The Global Battle.!!!

What is Resistance?

•Drug resistance refers to unresponsiveness of a microorganism to an antimicrobial agent.

•Drug resistance are of two types:---Natural Resistance---Acquired Resistance

Porins

Altered penicillin binding proteins

b-lactamases

MECHANISMS OF RESISTANCE

38

MECHANISMS FOR ACQUIRING RESISTANCE

CHALLENGES OF b-LACTAMASES 1940 : Introduction of penicillins 1940 : First description of b-lactamases published 1944 : Strains of staphylococcus aureus producing

b-lactamase 1960s : Clinical use of expanded spectrum penicillins - such as ampicillin and carbenicillin 1970s : plasmid mediated b-lactamases assumed prominence in

enterobacteriaceae and gram-negative bacteria 1980-90 : Development of broad-spectrum cephalosporins,

cephamycins, monobactams and carbapenems 1990 : Increased resistance among gram-negative bacteria with

inducible chromosomally-mediated b lactamases JAC (1993); suppl A: 1-8

Beta–lactamases

Beta-Lactamase Enzyme

Functional Classification

Group 1 (Cephalosporinases*)

Group 2 (Penicillinases,

Cephalosporinases)

Group 3 (Metalloenzymes*)

Group 4 (Penicillinases*)

* Not inhibited by Clavulanic Acid

Beta-Lactamase Enzyme

Molecular Classification

Serine Based

Class A Class C Class D

Metallo B-

lactamases

Class B

BETA-LACTAMASE INHIBITORS

• Resemble β-lactam antibiotic structure • Bind to β-lactamase and protect the antibiotic from destruction• Most successful when they bind the β-lactamase irreversibly • Three important in medicine:

» Clavulanic Acid» Sulbactam» Tazobactam