Cell Wall Synthesis Inhibitors (Penicillins) Course Coordinator Jamaluddin Shaikh, Ph.D. School of Pharmacy, University of Nizwa Lecture 2 September 19, 2011

Targets of Antibiotic Inhibition of cell wall synthesis Inhibition of protein synthesis Inhibition of nucleic acid replication and transcription Injury to plasma membrane Inhibition of synthesis of essential metabolites

Targets of Antibiotic

Classification of Cell Wall Synthesis Inhibitor Cell wall synthesis inhibitor antibiotics have two types β-Lactam antibiotic Other antibiotic

β-Lactam Antibiotic β-Lactam antibiotics have four classes Penicillin Cephalosporin Carbapenem Monobactam

Penicillin Penicillin is most widely effective antibiotic Few names of Penicillin class of antibiotic Amoxicillin Ampicillin Dicloxacillin Oxacillin Penicillin G Penicillin V

Why Penicillin called β-Lactam Antibiotics? Name of this antibiotic is because of the presence of β-lactam ring This ring can be cleaved by β-lactamase enzymes produced by bacteria This class of antibiotics kill bacteria by inhibiting bacterial cell wall synthesis

Structure of Penicillin Nucleus contains a β-lactam and a thiazolidine ring Metabolic transformation or chemical alteration of penicillin nucleus causes loss of all significant antibacterial activity Side chain affects the antimicrobial spectrum, stability to stomach acid, and susceptibility to bacterial degradative enzymes C NH CH O N CH3 COOH S b-lactam Thiozolidine Site of penicillinase action

Penicillin: History 1928: Alexander Fleming working at St Mary's Hospital in London first discovered penicillin 1940: Extracted and antibacterial effects analyzed 1941: First antibiotic used clinically

Penicillin: Mechanism of Action Interfere with the last step of bacterial cell wall Cell lysis can occur, either through osmotic pressure or through the activation of autolysins The success of a penicillin in causing cell death is related to the antibiotic's size, charge, and hydrophobicity Penicillin are effective against rapidly growing organisms that synthesize a peptidoglycan cell wall Consequently, they are inactive against organisms devoid of this structure, e.g., mycobacteria, protozoa, fungi, and viruses

Penicillin: Mechanism of Action, continued.. Details mechanisms of action: 1. Penicillin-binding proteins: Penicillin inactivate numerous proteins on the bacterial cell membrane These penicillin-binding proteins (PBPs) are bacterial enzymes involved in the synthesis of the cell wall Interfere with the last step of bacterial cell wall

Penicillin: Mechanism of Action, continued.. 2. Inhibition of transpeptidase Some PBPs catalyze formation of the cross-linkages between peptidoglycan chains Inhibit this transpeptidase-catalyzed reaction, thus hindering the formation of cross-links essential for cell wall integrity 3. Production of autolysins The antibacterial effect of a penicillin is the result of both inhibition of cell wall synthesis and destruction of existing cell wall by autolysins An autolysin is an enzyme that hydrolyzes (and breaks down) the components of a biological cell or a tissue in which it is produced

Penicillin: Pharmacokinetic Aspects Administration: Route of administration is determined by the stability of the drug to gastric acid and by the severity of the infection, e.g., oral, i.v., combine with other antibiotic Absorption: Most of the penicillin are incompletely absorbed after oral administration. However, amoxicillin is almost completely absorbed Distribution: Distribute well throughout the body. Penicillin cross the placental barrier Excretion: Excretion is through the tubular secretary system of the kidney as well as by glomerular filtration

Penicillin: Adverse Effects Penicillins are among the safest drugs. However, the following adverse reactions may occur Hypersensitivity is the most important adverse effect Diarrhea is a common problem Have the potential to cause acute interstitial nephritis Penicillins are irritating to neuronal tissue Hypersensitivity refers to undesirable reactions produced by the normal immune system Nephritis is inflammation of the nephrons in the kidneys

Classification: Based on Antibacterial Spectrum Penicillin with a narrow antibacterial spectrum: Acid labile penicillin Benzylpenicillin (Penicillin G) Acid stable penicillin Phenoxymethylpenicillin Antistaphylococcal penicillin Cloxacillin Extended spectrum penicillin: Ampicillin Amoxycillin Antipseudomonal penicillin Carbenicillin Ticarcillin

Penicillin G Drug of choice for: Adverse effects: Shortcomings: Streptococcal, pneumococcal, gonococcal infections, anthrax, diptheria, syphilis, tetanus Adverse effects: Anaphylaxis can occur (1 in 100,000 injections), always enquire about previous reaction before administration Skin rashes Shortcomings: Acid labile, inactivated in gastric acid Short half-life, frequent injections are required Development of resistant β-lactamase producing strain Narrow antibacterial spectrum Anaphylaxis is an acute multi-system severe type I hypersensitivity allergic reaction

Phenoxymethylpenicillin Acid stable, effective when given orally While useful for mild infections, it is not used in serious infections or with poorly sensitive bacteria Tablets are given on an empty stomach to improve absorption Cloxacillin Developed to overcome β-lactamase-producing strains Similar antibacterial spectrum to benzylpenicillin Used for the treatment of staphylococcal infections

Ampicillin/Amoxycillin Uses: Effective against most strains of E. coli, H. influenza and Salmonella Used for various chest infections, urinary tract infections Amoxycillin is more potent than ampicillin Both are susceptible to β-lactamases Adverse effects: Rashes are common and may appear after dosing has stopped Pharmacokinetics: Half life 1.5 h Renal excretion

Antipseudomonal Penicillins Uses: Expensive intravenous penicillins Useful against Gram-negative infections, with Pseudomonas Adverse effects: Rashes are common Pharmacokinetics: Half life 1.5 h Given intravenously every 4-6 h Renal excretion

Resistance to Penicillin Mechanism: Natural resistance to the penicillins occurs in organisms that either lack a peptidoglycan cell wall or have cell walls that are impermeable to the drugs β-lactamase enzymes hydrolyzes the β-lactam ring, which results in loss of bactericidal activity Decreased penetration of the antibiotic through the outer cell membrane prevents the drug from reaching the target PBPs