home Antibiotics, Pharmacology How Does Penicillin Work?

How Does Penicillin Work?


The antibacterial activity of penicillin, like all β-lactam antibiotics, is due to its inhibition of bacterial cell wall synthesis. The cell wall of both gram positive and gram negative bacteria is composed of peptidoglycan that protects against osmotic rupture. The cell wall of gram positive bacteria is a substantial layer 50 to 100 molecules in thickness, whereas in gram negative bacteria it is only one or two molecules thick. An outer membrane lipopolysaccharide layer, not found in gram positive bacteria, is present in gram negative species.

Mechanism of Action

Bacterial Cell Wall Structure
Bacterial Cell Wall Structure is formed by NAG and NAM. A pentapeptide chain is added to NAM and then NAG combines with NAG. The NAG-NAM complex is transported outside of the bacterial cell to form part of the peptidoglycan meshwork.

Penicillin belongs to a group of drugs known as “Cell Wall Inhibitors” whose function is to stop bacteria from producing its protective cell wall. Without the cell wall, bacteria are more susceptible to the harsh environment inside the human body and destruction by the body’s several immune defenses. Penicillin, in particular, functions by inhibiting enzymes that catalyze the final step in gram positive bacterial cell wall assembly, which is the formation of the cross-links that bridge the outer peptidoglycan layer and gives the bacteria its structural integrity.

Peptidoglycan is composed of long polysaccharide (sugar) chains of N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM) pentapeptide. The pentapeptide consists of amino acid residues alternating between L- and D- sterioisomers and terminating in D-alanyl-D-alanine. The pentapeptides are joined at the third amino acid, forming a crosslink between the polysaccharide chains. This transpeptidation reaction, along with other Penicillin Binding Protein (PBP) sites, are sensitive to inhibition by the penicillin classes. Blocking several PBP’s also can result in triggering cell lysis (cell death), making the penicillin class bactericidal (capable of killing bacteria). Basically, this drug inhibits the bacteria cell wall from forming which leads to death of the bacteria.

Classification of Penicillins

Penicillins can be classified into four functional classes: (1) natural penicillins; (2) penicillinase-resistant penicillins; (3) aminopenicillins; and (4) antipseudomonal penicillins (also classified as two structural classes: carboxypenicillins and ureidopenicillins).

Natural Penicillins

Penicillin binds and blocks transpeptidation, an important process in bacterial cell wall formation that joins the various NAM and NAG complexes together forming a protective meshwork.

Penicillin G and penicillin V are the natural penicillins. Penicillin G is administered intravenously or through intramuscular injection (think penicillin “G” associated with its usual site of injection, Gluteus Maximus) while penicillin V is available for oral use. Natural penicillins are mostly for gram positive organisms and spirochetes due to their inability to bypass the gram negative outer membrane or β-lactamase production. Penicillin G remains the primary agent for treatment of infections due to: Streptococcus pyogenes; penicillin-susceptible strains of Streptococcus pneumonia; enterocci; treatment of pneumococcal and meningococcal meningitis; streptococcal endocarditis; neurosyphilis; Streptococcus agalactiae; and Actinomyces. They are also used as prophylaxis against rheumatic fever.

Penicillinase-Resistant Penicillins

Penicillinase-resistant penicillins, also called “anti-Staphylococci penicillins,” are indicated solely for the treatment of infections caused by methicillin-susceptible strains of staphylocci. Methicillin, nafcillin, oxacillin, cloxacillin, dicloxacillin, flucloxacillin are penicillinase resistant, meaning they are not inactivated by bacterial enzyme penicillinase (due to a bulkier R-group).


Wikipedia https://en.wikipedia.org/wiki/Peptidoglycan#/media/File:Mureine.svg
NAG-NAM Meshwork of a gram positive bacteria. Courtesy of Wikipedia.

Ampicillin and Amoxicillin make up this class which “HEELPSS” (covers H. influenza, E. coli and Enterococci, L. monocytogenes, P. mirabilis, Salmonella and Shigella) amplify the use of penicillins to a wider spectrum of bacteria including both gram positive and gram negative. They are used for treatment of

upper respiratory tract infections, lower respiratory tract infections, bacterial gastroenteritis (ampicillin), and bacterial endocarditis, meningitis, and urinary tract infections. Amoxicillin has a better oral bioavailability than ampicillin, which is only absorbed 30% – 60% and decreases with food intake. This class is susceptible to bacteria β-lactamase and therefore are usually given in combination with clavulanic acid.


Pseudomonas Bacteria, Gram Negative Rods. Courtesy of Visuals Unlimited.

Ticarcillin, Carbenacillin and Piperacillin “Take Care of Pseudomonas” infections and like aminopenicillins are also susceptible to bacteria β-lactamase and are also given in combination with clavulanic acid, tazobactam or sulbactam. When used to treat Pseudomonas, they should be used in combination with another antipseudominal agent, typically an aminoglycoside. Carbenacillin is no longer used in the U.S. due to high dose requirements and potential for toxicity. Piperacillin is also active against Klebsiella spp., Enterobacter spp., Serratia marcescens, and Providentia.