Penicillin's Structure and Function

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  • Rachael Sim Hwee Ling

A Molecule that Shapes the World – C16H18N2O4S

The discovery of penicillin has revolutionized the world of medicine and saved millions of lives. Penicillin is a group of antibiotics derived from Penicillium fungi [1]. Antibiotics are specific substances derived from living organisms that can inhibit the life processes of other organisms [2]. Penicillin is effective against a range of bacteria such as staphylococciand streptococci and bacteria causing diseases like meningitis and gonorrhea [3]. Unlike sulfanilamide which is toxic to the kidney, penicillin has no harsh effects. It is non-irritating and can be applied to tissues directly [4]. During World War II, the administration of penicillin to the wounded soldiers greatly reduced their chanceS of injury infection and raised their survival chances in the interim time between the wounding and surgery (14 hours for the Allied Forces), thus dramatically reducing the need for amputations and the death toll from infected wounds [5]. Today, penicillin is still commonly used to treat conditions. Penicillin is often prescribed after dental surgery to prevent infections [6].

The diseases and infections mentioned above are caused by bacteria. Almost all bacteria have cell walls made up of peptidoglycan, a rigid but elastic structure, that protects the underlying protoplast from mechanical damage and prevent it from bursting under osmotic pressure. Peptidoglycan is made up of long polysaccharide chains that are cross-linked via flexible peptide bridges [7]. The synthesis of bacterial cell wall is catalyzed by the enzyme transpeptidase. Such synthesis is essential to the growth, cellular reproduction and maintaining the structure of bacteria.

In 1965, Tipper and Strominger hypothesized that penicillin kills bacteria by blocking the action of the transpeptidase that catalyzes the last step of synthesis which involves the cross-linking of different peptidoglycan chains, thus inhibiting the synthesis of the cell wall [8]. Water then enters the cell causing it to swell and explode. This essay will discuss how penicillin’s shape, structure, instability enable it to inhibit the action of transpeptidase, examine the science behind penicillin’s reaction, how the structure and size influence its effectiveness and the significance of the lack of symmetry.

Penicillin structure consists of a thiazolidine ring fused to a β-lactum ring to which a variable R group is attached by a peptide bond. (Fig 1) Penicillin G (Fig 2), which has a benzyl side-chain, is often regarded as the prototype of the class as it is one of the first-generation penicillin that can be obtained directly from the fungi. It is the most potent of the class against susceptible gram-positive bacteria and is still widely used.[9] Penicillin G is only effective against gram-positive bacteria in which the transpeptidases are directly accessible.

Fig 1: General Penicillin molecule with

R side chain, 3 chiral centres (*) and

a β-lactum ring (blue)

C:UsersLeslieDesktopPenicillin g use.png

Fig 2: Natural penicillin-G where R = benzyl group

Fig 3: D-Alanyl-D-alanine which closely resembles penicillin (In D-amino acid, with the H atom pointing up and looking down from the H atom and moving anti-CW, the amino acid has the order COOH, R, NH2)

One explanation about the mechanism of action of penicillin is that it mimics the shape and structure of the D-alanine-D-alanine termini of bacterial peptidoglycan (the usual substrate) and is thus recognized by transpeptidases [10]. The transpeptidase enzyme reacts preferentially and binds irreversibly with penicillin. The penicilloyl-enzyme formed is stable and does not react any further [11]. The free COOH group present mimics that of terminal carboxyl of D-alanine-D-alanine and is needed for penicillin to bind at the active site [12]. The similarities in their molecular structures can be clearly observed in Fig1 and Fig3. Furthermore, as penicillin lacks symmetry, its mirror images are non-super-imposable. In order for penicillin to be biologically active, the 3 chiral centres in penicillin must be in the configuration in Fig1 [13]. As penicillin’s activity is stereo-dependent, penicillin synthesized must be enantiopure and the arrangement of the groups relative to one another should resemble that of D-alanine-D-alanine. This also explains penicillin non-toxicity. D-alanine only occurs in the cell wall of bacteria and all the proteins within our body are built up from L-amino acids. Hence, penicillin kills bacteria but will not adversely affect humans. [14]

Another explanation also relates to the structure of penicillin and the instability of the cyclic amide in β-lactum ring which is fused to the thiazolidine ring. Research by Strominger has shown that the activity of penicillin is due to the inherent strain of the four-membered ring or to the reduced amide resonance [15]. In the four-membered ring, the C and N atoms are forced to have a bond angle of approximately 90° which is far below the preferred bond angle for singly-bonded sp3 hybridised carbon and nitrogen atoms (109.5°) and doubly-bonded sp2 hybridised carbon atom (120°). This put the small ring under great ring strain which is further aggravated by the five-membered thiazolidine ring fused with it. X-ray crystallography has also showed that the two fused rings and the amide bond is non-planar. This leads to a loss of resonance stabilization normally found in these amide bonds [16]. These make the amide group more reactive. Penicillin acylates the enzyme and form an open chain compound to relieve the strain.

Furthermore, it is hypothesized that the –COOH group in penicillin’s structure contributes to penicillin’s widely varying acylating ability and its ability to travel through bodily fluids unaltered and only target transpeptidase in bacteria. Experimental data obtained from inelastic neutrons and quantum chemical theory suggests that the activity of penicillin is pH dependent [17]. Under physiological conditions (pH = 7.4), penicillin’s -COOH group is deprotonated. As COO and the lone pair of electrons of N are on the same face of the molecule, the COO will repel the lone pair of electrons on the N atom. This shortens the amide bond, increases its strength and decrease the acylating power of the lactam ring [18]. When near the active site of transpeptidase, COO group is protonated and the β-lactum amide bond regains its strong acylating power [19]. The 2 CH3 group is also important for activation as research has found no activity for penicillin analogues with these groups removed. [20]

At the active site, the science of reaction is as follows. The nucleophilic –OH group of the serine residue attacks and opens the ring. A covalent bond is formed between the serine on the enzyme and the penicillin molecule [21], irreversibly inhibiting the normal function of the enzyme and kills the bacterial cell.

The R group in the penicillin structure determines the effectiveness of the penicillin drug. Penicillin-G cannot be consumed orally as gastric acid will catalyze the hydrolysis of the highly unstable β-lactum ring, destroying its antibiotic properties. The β-lactum ring is also susceptible to attack by O atom of the neighboring carbonyl group. To prevent this, we can choose an electron withdrawing R group to decrease the nucleophilicity of the carbonyl oxygen on the acyl side chain to reduce the self destructive mechanism[22]. To avoid degradation by penicillinase enzyme, we can choose a bulky R group as a steric shield.

The small size of penicillin molecules increases their potency as it enables them to penetrate the entire depth of the cell wall.

In conclusion, penicillin-G is a molecule that was cleverly designed molecule by nature. All features in its structure – its bicyclic system, unstable β-lactum ring, COOH group, stereochemistry and size is essential and influence its effectiveness. They enable penicillin to irreversibly react with transpeptidases, kill harmful bacteria and by doing so, save lives and shape the world.


[1] penicillin. (n.d.)The American Heritage® Medical Dictionary. (2007). Retrieved January 31 2015 fromhttp://medical dictionary.thefreedictionary.com/penicillin

[2] antibiotic. (n.d.)The American Heritage® Medical Dictionary. (2007). Retrieved January 31 2015 fromhttp://medical-dictionary.thefreedictionary.com/antibiotic

[3] penicillin. (n.d.)Dorland’s Medical Dictionary for Health Consumers. (2007). Retrieved January 31 2015 fromhttp://medical-dictionary.thefreedictionary.com/penicillin

[4] Fleming, A. (1929). On the antibacterial action of cultures of a penicillium, with special reference to their use in the isolation of B. influenzae.British journal of experimental pathology,10(3), 226.

Couteur, P., & Burreson, J. (2004). Wonder Drugs. InNapoleon’s buttons: 17 molecules that changed history. Jeremy P. Tarcher/Penguin: New York.

[5] Medicine and World War Two. (2014, January 1). Retrieved January 31, 2015, from http://www.historylearningsite.co.uk/medicine_and_world_war_two.htm

[6] Ross-Flanigan, Nancy; Uretsky, Samuel. “Penicillins.”Gale Encyclopedia of Children’s Health: Infancy through Adolescence. 2006. Retrieved January 31, 2015 from Encyclopedia.com:http://www.encyclopedia.com/doc/1G2-3447200431.html

[7] Graumann, P. (2007).Bacillus: Cellular and molecular biology(p. 333). Norfolk: Caister Academic Press.

[8] Tipper, D., & Strominger, J. (1965.). Mechanism Of Action Of Penicillins: A Proposal Based On Their Structural Similarity To Acyl-D-alanyl-D-alanine.Proceedings of the National Academy of Sciences,1133-1141

[9] Penicillins. (n.d.). Retrieved January 31, 2015, from http://www.emedexpert.com/compare/penicillins.shtml#4

[10]Tipper, D., & Strominger, J. (1965.). Mechanism Of Action Of Penicillins: A Proposal Based On Their Structural Similarity To Acyl-D-alanyl-D-alanine.Proceedings of the National Academy of Sciences,1133-1141.

[11] Berg, J., & Tymoczko, J. (2002). Enzymes: Basic Concepts and Kinetics. InBiochemistry(5th ed.). New York: W.H. Freeman.

[12] Tipper, D., & Strominger, J. (1965.). Mechanism Of Action Of Penicillins: A Proposal Based On Their Structural Similarity To Acyl-D-alanyl-D-alanine.Proceedings of the National Academy of Sciences,1133-1141.

[13] Bentley, R. (2004). The Molecular Structure of Penicillin.Journal of Chemical Education,1462-1462.

[14] Otter, C. (2008). Chemical ideas (3ed. ed.). Oxford [u.a.: Heinemann Educational.

[15] Strominger, J.L. (1967) . Enzymatic reactions in bacterial cell wall synthesis sensitive to penicillins, cephalosprins and other antibacterial agents. Antibiotics, 705–713

[16] J. C. Sheeman, The enchanted Ring: The Untold Story of Penicillin, The MIT Press, Cambridge, Massachusetts, 1982

J. R. Johnson, R. B. Woodward and R. Robinson, in The Chemistry of Penicillin, ed. H. T. Clarke, J. R. Johnson and R. Robinson, Princeton University Press: Princeton, New Jersey, 1949, ch. 15, pp. 443–449.

[17],18,19 Mucsi, Z.; Chass, G.A.; Abranyi-Balogh, P.; Jozart, B.; Fang, D.-C.; Ramirez-Cuesta, A.J.; Viskolcz, B.; Csizmadia, I.G. Penicillin’s catalytic mechanism revealed by inelastic neutrons and quantum chemical theory. Phys. Chem. Chem. Phys. 2013, 15, 20447–20455

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[19]

[20] S. Wolfe, J. C. Godfrey, C. T. Holdrege and Y. G. Perron, J. Am. Chem. Soc., 1963, 85, 643 ; S. Wolfe, J. C. Godfrey, C. T. Holdrege and Y. G. Perron, Can. J. Chem., 1968, 46, 2549.; J. Hoogmartens, P. J. Claes and H. Vanderhaeghe, J. Med. Chem., 1974, 17, 389;T. K. Vasudevan and V. S. R. Rao, Int. J. Biol. Macromol., 1982, 4, 219.

[21] Yocum, R., Strominger, J., Rasmussen, J., & Waxman, D. (1979). Mechanism of Penicillin Action: Penicillin and Substrate Bind Covalently to the Same Active Site Serine in Two Bacterial D-alanine Carboxypeptidases.Proceedings of the National Academy of Sciences,2730-2734.

[22] Proctor, P., Gensmantel, N., & Page, M. (1982). The chemical reactivity of penicillins and other ?-lactam antibiotics.Journal of the Chemical Society, Perkin Transactions 2,1185-1185.

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