• Penicillin G and Penicillin V

  Penicillin G and Penicillin V Audio Overview

  • Penicillin overview

    • Penicillin Structural Elements

      Penicillin is classified as a β-lactam antibiotic. The structure features a ß-lactam ring characterized by a cyclic amide in which the nitrogen atom is bonded to the carbonyl group's β-carbon atom. In the case of penicillin the nitrogen atom is a constituent of the thiazolidine ring (See below)

      The combined structure (above) is a "penam ring." Penicillin, independent of the form, will contain a penam ring. The difference between one penicillin in another type resides in differing R groups.

      Attribution ChemTalk Penicillin: A Biochemical Perspective. https://chemistrytalk.org/penicillin-a-biochemical-perspective/

       

    • Penicillin Mechanism of Antibiotic Action

      "All but two types of bacteria (Mycoplasma and L-form bacteria) have a cell wall. The cell wall, in bacteria that have it, is reinforced by an outer membrane made of peptidoglycan. Each peptidoglycan monomer consists of two sugars: N-acetylmuramic acid (NAM), which is also attached to a tetrapeptide, and N-acetylglucosamine (NAG). The four peptides within the tetrapeptide are diverse across different bacterial species.  Tetrapeptide chains of individual monomers cross-link to form a mesh-like crystal lattice around the exterior of the bacterial cell." 13 (See figure below)

      Peptidoglycan monomer in which the R group (red) represents a tetrapeptide.13

      "The peptidoglycan polymer, with the monomer highlighted in red. Note the tetrapeptides (multicolored circles) attached to the NAM in each monomer. The tetrapeptides chains of parallel monomers are cross-linked (green), forming the lattice."13 NAM: N-acetyl muramic acid NAG: N-acetylglucosamine The NAG monomers link to NAM, creating the disaccharide unit. These units alternate, forming long chains utilizing beta-1, 4-glycosidic bonds.

      Attribution ChemTalk Penicillin: A Biochemical Perspective. https://chemistrytalk.org/penicillin-a-biochemical-perspective/

    • How Penicillin Disrupts the Bacterial Cell Outer Membrane

      Peptidoglycans maintain bacterial cell structure by surrounding the bacterial cell with a scaffolding-like structure. Bacterial cell survival requires stability of this structure which depends on cross-linking the tetrapeptides to form the peptidoglycan layer.13  This cross-linking specifically depends on the activity of an enzyme, DD-transpeptidase, and penicillins inhibit the activity of this enzyme by forming a stable penicilloyl-enzyme intermediate.13,14 DD transpeptidase may be referred to as serine-typeD-Ala-D-Ala carboxypeptidase. In recognition of the interaction between the transpeptidase and penicillin, DD-transpeptidase is commonly referred to as PBP or Penicillin-Binding Protein.14

     

    • Structure of Steptomyces K15 DD-Transpeptidase

      Attribution Omargs10, CC BY-SA 4.0 <https://creativecommons.org/licenses/by-sa/4.0>, via Wikimedia Commons https://commons.wikimedia.org/wiki/File:DD-Transpeptidase.png (March 2, 2016).

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      Penicillin G (2D)

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      Penicillin G (3D)

       

    • Penicillin V (2D)

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      Penicillin V (3D)

     

    • Penicillins, and all β-lactam antibiotics, are defined by their unique chemical architecture.

      • The core of the penicillin molecule is a bicyclic system known as the penam nucleus. ^1,2  This structure consists of a highly strained, four-membered ring called a β-lactam ring, which is fused to a five-membered thiazolidine ring. ^1,2  

      • The β-lactam ring, a cyclic amide where the nitrogen atom is attached to the β-carbon relative to the carbonyl group, is the critical functional moiety responsible for the antibiotic's bactericidal activity.³

        • The inherent ring strain of this structure makes it chemically reactive and susceptible to nucleophilic attack, a property that is central to its mechanism of action.⁴

        • Penicillin Structure⁴

          Attribution The beta-lactam ring is essential for penicillin activity.4  The carbon atom C of the lactam C=O is very susceptible to nucleophilic attack. The carboxylic acid moiety contributes to the binding of penicillin to the active site of the transpeptidase enzyme. The reactivity of the beta-lactam ring results in penicillin being susceptible to inactivation following nucleophilic acyl substitution reactions, forming a penicilloic acid. This form does not exhibit antibiotic activity. Enhancement of penicillin stability may be accomplished by electron-withdrawing substituents at the side chain. The effect of the substitution is to make the amide carbonyl less reactive.4 An example of this effect can be illustrated using the to antibiotics under present consideration, Penicillin G and Penicillin V.   Penicillin G and Penicillin V: Basis of Differences in Drug Stability when exposed to Stomach Acid4 Note the additional oxygen associated with Penicillin V (green). This oxygen has the effect of decreasing nucleophilicity of the amide carbonyl group, reducing its reactivity with the internal beta-lactam ring. A consequence of addition of this oxygen (green) is that Penicillin G is sufficiently stable in the acidic stomach environment such that this medication may be orally administered. By contrast, lacking this oxygen, Penicillin V can not maintain its structure in the acidic stomach environment and therefore must be administered by the intravenous route of administration. The top figure is a slight modification of the first figure in reference 4; whereas the second figure above corresponds to the fourth figure in reference 4, Noted below. Futurelearn Mode of Action of Penicillin. https://www.futurelearn.com/info/courses/everyday-chemistry/0/steps/22314 Future Learn:  https://www.futurelearn.com/

        • Variations in the acyl side chain attached at the 6-position of this 6-aminopenicillanic acid core determine the specific characteristics of each penicillin, including its antimicrobial spectrum, stability, and susceptibility to bacterial resistance mechanisms.^5,6  

    • Penicillin G: Structure

      • Chemically definition(2S,5R,6R)-3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid.^7,9  

        • Its empirical formula is C₁₆H₁₈N₂O₄S.^7,8  

      • A defining feature is the benzyl (phenylacetyl) group that constitutes its side chain.⁹

        • Penicillin G (Benzylpenicillin)⁹

          Attribution Benzylpenicillinic (Molecule of the Week Archive; July 9, 2018) American Chemical Society https://www.acs.org/molecule-of-the-week/archive/b/benzylpenicillin.html

        • Penicillin G has also been known as benzylpenicillin or benzylpenicillinic acid.⁹

          • In its free acid form, penicillin G is a white crystalline powder that is only sparingly soluble in water and is chemically unstable, particularly in aqueous solutions.

            •  These physicochemical limitations render the free acid impractical for clinical use.⁹

          • To overcome limitations with the free acid form, penicillin G is formulated for example, as its potassium salts, which are much more water-soluble and stable, allowing for parenteral (intravenous or intramuscular) administration.¹⁰

            •  However, even in these salt forms, aqueous penicillin G is excreted by the kidneys with extreme rapidity, resulting in a very short therapeutic half-life that necessitates frequent dosing.¹⁰ 

            • To address this pharmacokinetic challenge, long-acting "depot" or "repository" formulations were developed.

              • These involve creating salts with large organic bases, such as procaine or benzathine, which are far less soluble in water.^11,12

              • When injected intramuscularly, these salts form a depot from which the active penicillin G is slowly hydrolyzed and absorbed into the circulation over an extended period.

              • Procaine penicillin G provides therapeutic concentrations for approximately 24 hours¹¹, while benzathine penicillin G can maintain low but effective levels for two to four weeks.¹²

August, 2025