Penicillin, the most important antibiotic, was first extracted from the mould Penicillium notatum. Subsequently, a mutant of a related mould, P. chrysogenum, was found to give the highest yield of penicillin and is employed for the commercial production of this antibiotic. Penicillin belongs to a group of antibiotics called β-lactam antibiotics. The basic structure of the penicillins consists of a thiazolidine ring fused with a βlactam ring, which is essential for antibacterial activity. These two rings constitute the fundamental nucleus of all the penicillins, namely, 6-amino penicillanic acid (6-APA). Various semisynthetic penicillins are produced by altering the composition of the side chain attached to the 6-APA nucleus. Both the 6-APA nucleus and side chain are essential for antibacterial activity.
Nomenclature of penicillin:
(a) There are two types of numbering for the fused bicycling system of penicillin: whether which atom is number one Sulfur or Nitrogen.
(b) Penam nucleus is used in naming, which comprises a bicyclic system with the amide carbonyl group. Penicillin is named as 6-acylamino-2,2-dimethylpenam-3-carboxylic acid.
(c) Penicillanic acid nucleus: Which includes the 2,2-dimethyl and 3-carboxyl groups. Penicillin is named as 6- carbonylaminopenicillanic acid.
(d) Penicillin nucleus: Which includes 6-carbonyl aminopenicillanic acid. So Penicillin G is named benzylpenicillin if R is benzene ring.
Stereochemistry of penicillin:
The stereochemistry of penicillin refers to the spatial arrangement of atoms in the molecule, particularly around the beta-lactam ring. Penicillins are chiral molecules, meaning they have at least one carbon atom bonded to four different substituents, leading to the existence of stereoisomers. The stereochemistry of penicillin is crucial because different stereoisomers can have varying pharmacological properties, including efficacy and toxicity.
- Beta-Lactam Ring: The beta-lactam ring is a four-membered lactam ring with an amide functional group. This ring structure is critical for the antibiotic activity of penicillins.
- Alpha Carbon: The alpha carbon (C-2) of penicillin is a chiral centre, providing two possible enantiomers: (R) and (S). The (R) and (S) configurations refer to the spatial arrangement of the substituents around this carbon atom.
- Side Chain: Penicillins have a variable side chain attached to the alpha carbon. The side chain determines each penicillin derivative’s specific properties and spectrum of activity.
- In natural penicillins like penicillin G, the side chain contains a beta-lactamase-sensitive group, making them susceptible to bacterial enzymes that can break down the antibiotic.
- Semisynthetic penicillins, such as amoxicillin and ampicillin, have modified side chains that increase their stability against beta-lactamases and broaden their spectrum of activity.
- Stereoisomers: The two enantiomers of penicillin differ in their biological activity. For example, penicillin’s (R) enantiomer is generally more active against bacterial targets than the (S) enantiomer. However, the (S) enantiomer may contribute to side effects or toxicity.
- Clinical Implications: The stereochemistry of penicillin affects its pharmacokinetics, pharmacodynamics, and interactions with target enzymes. The differences in stereochemistry can influence factors such as drug potency, stability, and resistance to bacterial enzymes.
- For example, penicillin’s (R) enantiomer generally has a greater affinity for penicillin-binding proteins (PBPs), the bacterial enzymes targeted by penicillins.
- Some stereoisomers may be more resistant to degradation by bacterial beta-lactamases, enhancing their efficacy.
Overall, understanding the stereochemistry of penicillin is essential for optimising its therapeutic effects and minimizing side effects. It allows pharmaceutical chemists to design penicillin derivatives with improved properties, such as increased stability and a broader spectrum of activity, contributing to developing more effective antibiotics.
Mechanism of action of Penicillin:
Penicillin and other beta-lactam antibiotics contain a four-membered beta-lactam ring. They work by irreversibly binding to DD-transpeptidase, an enzyme involved in bacterial cell wall synthesis. This binding inhibits the enzyme’s cross-linking activity, disrupting cell wall formation and leading to bacterial cell lysis and death.
Fig: General Machemis of action of Penicillin
Fig: General Machemis of action of Penicillin