How Does Penicillin Work?

Introduction
Penicillin was first discovered by Alexander Fleming in 1928. It was the first
chemical compound with antibiotic properties. Antibiotics are a type of drugs
that use in the treatment of bacterial infections. There are two types of
antibiotics: bactericidal and bacteriostatic. Bactericidal antibiotics interfere
with the synthesis of the bacterias cell wall and or cell content, which
ultimately kill the bacteria. On the other hand, bacteriostatic antibiotics only
inhibit the growth of the bacteria. They do not kill the bacteria, but they stop
the spread of the bacteria.

Chemistry
Penicillin is a Thiazolidine ring that is attached to a beta-lactam ringa four
membered nitrogenous ring. The beta-lactam ring contains a secondary
amino acid group, which is used to determine the types of penicillin. The
combination of the thiazolidine ring and beat-lactam is very essential to
penicillins biologic activities.

Figure 1. Chemical structure of penicillin

Classification of Penicillin
Penicillin is divided into two broad categories: natural and semisynthetic.
Natural penicillin is known as Penicillin G. Semisynthetic Penicillin is
subdivided into five small classes:
1) Acid resistant
a) Aenicillin V
2) Penicillinase-resistant
a) Methicillin and Cloxacillin
3) Aminopenicillin
a) Ampicillin, Amoxicillin, and Bacampicillin
4) Antipseudomonal penicillin
a) Cerbenicillin, Ticarcillin, Piperacillin, and Mezlocillin
5) Beta-lactumase inhibitors
a) Clavulanic acid, Sulbactam Tazobactam
The active ingredient in penicillin is derived from Penicillium fungi. It is most
effective against bacterial infections caused by Staphylococci and
Streptococci bacteria. Penicillin is considered a beta-lactam antibiotic
because it contains a beta-lactam ring (Figure 1). The beta-lactam directly
binds to the enzyme that helps with the cross-linkage of the peptidoglycan in
the cell wall, causing the cell wall to weaken. Since most of the bacteria have
high internal osmosis pressure, the cell will lyse when there is a slight
change in the external osmosis pressure, which will lead to cells death. This
is also why penicillin is considered a bactericidal antibiotic.

Mechanism of Action
Penicillin kills the bacteria by interfering with the transpeptidation reaction of
the bacterial cell walla process at which the components of the cell wall
cross linked. The cell wall of bacteria has three main components: crosslinked polymer of polysaccharides, polypeptides, and peptidoglycan. The
cross-linked polymer of the polysaccharides are composed of alternating
amino sugars, N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM).
The polypeptides in the bacterial cell wall is very unique because it must
terminate in D-alanyl-D-alanine. Peptidoglycan is a sugar crystal lattice
structure that is made up of alternating NAG and NAM, linked by short
peptide chains of three to five amino acids.

Figure 2. Bacteria Cell Wall

Figure 3. Structure of Peptidoglycan

The Penicillin binding protein (PBP) removes the terminal alanine of the
polysaccharides in the process of forming a cross-link with a nearby peptide.
PBP then signals the beta-lactam to bind to the altered terminal of the
polypeptide.
The beta-lactam ring on the penicillin, a structural analog of the natural DAla-D-Ala substrate, binds to the enzyme DD-transpeptidase in the cell wall.
Once the DD-transpeptidase is inactivated, the cross-linkage between
peptidoglycan cannot be catalyzed. This causes the cell wall of the bacteria

to weaken and an imbalance of the osmosis pressure. The osmosis pressure

will continue to increase within the cell because there is no cell wall to
provide protect to the cell. The bacteria undergoes cytolysis and die when
the osmosis pressure become too high.

Figure 4. Mechanism of Action of Penicillin

Resistance
Unfortunately, there are two ways that bacteria can become resistant to the
treatment of penicillin:
1. Drug inactivation or modification
2. Alternation of target site.
Most of drug inactivation resistance occurs when patients built up a
resistance for penicillin G. Bacteria with a resistance to penicillin G produces
an enzyme called beta-lactamase. When beta-lactamases are released into
the cell wall, the peptidoglycan will add an acetyl or phosphate group to its
terminal. This reduces penicillins ability to bind to the end of the
polypeptide, thus synthesis of the cross-linked between peptidoglycan is
uninterrupted.

Figure 5. Mechanism of Drug Inactivation

Alteration of target site resistance is commonly seen in patients with MRSA
infection. The MSRA bacteria has the altered activation site in penicillin
binding protein. Since the activation site in penicillin binding protein undergo
a conformational change, the beta-lactam ring of penicillin can no longer
bind to the protein, thus penicillin has no effect on the bacteria.

Figure 6. Mechanism of Alteration of Target Site