TGES

A study on the drugs used for the treatment of Pneumonia.

Penicillins (Penicillin and Amoxicillin)
Saurav Kini Bij Javia Khyati Kansagra 2013-2014

The project in based on two drugs- Penicillin and Amoxicillin - The history, commercial manufacturing process, laboratory manufacturing process, the mode of action, the chemical structure (Including the bonding involved) and a few other topics which are specific to the drugs studied.

Project Pneumonia (Chemistry)

INDEX
Sr.no 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 1.10 1.111.13 1.14 1.15 1.16 1.17 1.18 1.19 1.20 1.21 Topic Pnemonia A brief introduction Penicillin The history of penicillin Chemical structure Specific structure Biosynthesis of Pen G Commercial production of Pen V Sheehans synthesis Aminopenicillin History of Amoxicillin Chemical structure Dosage of Amoxicillin, Pen V and Pen G Chemical synthesis Grossmans process Enzymatic synthesis of Amoxicillin -lactam antibiotics Mechanism of action Potency of -lactam antibiotics Resistance of -lactam antibiotics Augmentin (Amoxicillin- Clavulanate) 2 2-3 3 3-4 5-6 7 8 9 9-10 10 11 12 13 14 15 16 17 18-19 20 21 Page No.

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1.0. Pneumonia (A brief Introduction)

s Both of these are Gram-Positive bacteria (For information regarding Gram-positive bacteria refer notes at the end of the project).1 thus the most effective antibiotics for bacterial pneumonia are - lactams (details will be discussed ahead). The two - lactam antibiotics which we are going to discuss are Penicillin and Amoxicillin. The reason we chose Penicillin, even though it is usually not prescribed anymore due to various long term and short term side effects, for its historical significance and Amoxicillin as it as a Aminopenicillin. Another drug that we decided to include in the project, although not in much detail is Augmentin- a combination of Amoxicillin and Clavulanate. The reason for taking up Augmentin will be discussed ahead. Over the years various strains of streptococcus pneumonia have developed resistance to - lactam antibiotics, thus, Augmentin is a modification of amoxicillin with clavulanate which is not affected by - lactamase * (will be discussed)

1.1. Penicillin(abbreviated PCN or pen)

Penicillin is a group of antibiotics derived from Penicillium fungi. Penicillin antibiotics are historically significant because they are the first drugs that were effective against many previously serious diseases, such as syphilis, and infections caused by staphylococci and streptococci. Penicillins are still widely used today, though many types of bacteria are now resistant. All penicillins are -lactam antibiotics (will be discussed later) and are used in the treatment of bacterial infections caused by susceptible, usually Gram-positive2, organisms.They include penicillin G, procaine penicillin, benzathine penicillin, and penicillin V (Or VK).Penicillin VK is Penicillin V Potassium, the potassium salt of penicillin V. For Pneumonia, to be specific against Streptococcus pneumonia (i.e. Bacterial pneumonia), Penicillin G (benzylpenicillin)and Penicillin V (or VK) (phenoxymethylpenicillin) were used earlier, before penicillin-resistant strains of pneumonia developed. Phenoxymethylpenicillin is less active against Gram-negative bacteria2 than benzylpenicillin. Benzylpenicillin is given by injection (parenterally), but

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phenoxymethylpenicillin is given orally. Benzylpenicillin, commonly known as penicillin G, is the gold standard type of penicillin. 'G' in the name 'Penicillin G' refers to 'Gold Standard'. Penicillin G is typically given by a parenteral route of administration (not orally) because it is unstable in the hydrochloric acid of the stomach. Because the drug is given parenterally, higher tissue concentrations of penicillin G can be achieved than is possible with phenoxymethylpenicillin. (Refer above paragraph) These higher concentrations translate to increased antibacterial activity.

1.2. The History of Penicillin- Serendipity!

Penicillin was first noticed by a French medical student, Ernest Duchesne, in 1896. Penicillin was re-discovered by bacteriologist Alexander Fleming working at St. Mary's Hospital in London in 1928. He observed that a plate culture of Staphylococcus had been contaminated by a blue-green mold and that colonies of bacteria adjacent to the mold were being dissolved. Curious, Alexander Fleming grew the mold in a pure culture and found that it produced a substance that killed a number of disease-causing bacteria. Naming the substance penicillin, Dr. Fleming in 1929 published the results of his investigations, noting that his discovery might have therapeutic value if it could be produced in quantity. This serendipitous observation began the modern era of antibiotic discovery. The development of penicillin for use as a medicine is attributed to the Australian Nobel laureate Howard Walter Florey, together with the German Nobel laureate Ernst Chain and the English biochemist Norman Heatley. Well, as Fleming discovered penicilliums staphylococcus repressing power by a fortuitous accident, in 1930, Penicillin was first put into medical use by, Cecil George Paine, a pathologist at the Royal Infirmary in Sheffield, attempted to use penicillin to treat sycosis barbae, eruptions in beard follicles, but was unsuccessful. A very important part in the history of penicillins was Dorothy Hodgkins discovery of the three-dimensional structure of Penicillin.

1.3. Chemical structure

Penicillin is a group of antibiotics which include many antibiotics derived from the penicillium fungus, in this report, we are going include the most often penicillin drugs used for Pneumonia (CAP Community acquired pneumonia) natural penicillins

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Project Pneumonia (Chemistry)

(Penicillin V and Penicillin G), as discussed in the introduction. (Refer 1.0.) The general/core structure of penicillin is characterized by a penam ring. A penam ring has the molecular formula R-C9H11N2O4S, where R is the variable side chain that differentiates the penicillins from one another (For benzylpenicillin, R = Ph-CH2). The penam core has a molecular weight of 243 g/mol, with larger penicillins having molecular weights near 450. The key structural feature of the penicillins is the four-membered -lactam ring; this structural moiety is essential for penicillin's antibacterial activity. The -lactam ring is itself fused to a five-membered thiazolidine ring. The fusion of these two rings causes the -lactam ring to be more reactive than monocyclic -lactams because the two fused rings distort the -lactam amide bond and therefore remove the resonance stabilisation normally found in these chemical bonds.

The Core structure of a natural penicillin

1.4. Specific Structures

Penicillin G (G- stands for Gold standard) Molecular Formula: C16H18N2O4S
IUPAC name: (2S,5R,6R)-3,3-Dimethyl-7-oxo-6-[(phenylacetyl)amino]-4-thia-1-

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azabicyclo[3.92.0]heptane-2-carboxylic acid. Average molecular mass: 334.390106Da (Dalton). Other names(Brand names): Also known as: Benzylpenicillin, Pencillin G, Pfizerpen, Benzopenicillin, Abbocillin, Benzylpenicillin G, Dropcillin, Gelacillin, Liquacillin,Scotcil, Cilloral, Liquapen, Permapen, Pfizerpen, Penicillin, Bicillin LA, Pfizerpen G, Penicillin-2, Pentids '200', Pentids '250', Pentids '400', Pentids '800', Penicillin g sodium, Benzathine Penicillin, Penicillin G potassium, Benzylpenicillin Sodium, Benzylpenicillin Potassium, Benzathine Benzylpenicillin. Structure:(Folded envelope shape)

R=Benzyl group

The basic structure of Penicillin G is exactly what is given for the general formula of penicillin.A penam ring has the molecular formula R-C9H11N2O4S, where R is the variable side chain that differentiates the penicillins from one another (For benzylpenicillin, R = Ph-CH2).(As shown above).The key structural feature of the penicillins is the fourmembered -lactam ring; this structural moiety is essential for penicillin's antibacterial activity. The -lactam ring is itself fused to a five-membered thiazolidine ring. The same is present in all penicillins and Benzylpenicillin or Penicillin G is no exception.

Penicillin V(Phenoxymethylpenicillin)
[V stands for Vesco- which is latin for to feed as Penicillin V is an Oral drug] Molecular Formula: C16H18N2O5S Average mass: 350.389496 Da (Dalton).

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IUPAC: (2S,5R,6R)-3,3-Dimethyl-7-oxo-6-[(phenoxyacetyl)amino]-4-thia-1azabicyclo[3.2.0]heptane-2-carboxylic acid. Other names: Phenomycilline, Beromycin, Phenopenicillin, Fenospen, Ora.cillin, Penicillin phenoxymethyl, V-Cillin, Phenoxymethylpenicillin, Phenocillin Structure: Penicillin V is administered as Penicillin VK, Penicillin V is the phenoxymethyl analog of penicillin G. Penicillin V potassium is the potassium salt of penicillin V. Penicillin V Potassium is designated chemically as 4-Thia-1-azabicyclo [3.2.0] heptane2-carboxylic acid, 3,3-dimethyl-7-oxo- 6-[(phenoxyacetyl)amino]-, monopotassium salt, [2S-(2,5,6)]-. The following two structures are Penicillin V(Left) and Penicillin VK(Right) .

The hydrogen atom in Phenoxymethylpenicillin is replaced by a potassium atom in Penicillin VK.In penicillin V the R- group is attached is Ph O CH2. The same applies to penicillin

VK.

The replaceable group in Penicillin V is illustrated above.

1.5. Biosynthesis
The first step is the condensation of three amino acidsL--aminoadipic acid, Lcysteine, L-valine into a tripeptide. Before condensing into the tripeptide, the amino acid L-valine must undergo epimerization to become D-valine. The condensed tripeptide is

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Project Pneumonia (Chemistry)

named -(L--aminoadipyl)-L-cysteine-D-valine (ACV). The condensation reaction and epimerization are both catalyzed by the enzyme -(L--aminoadipyl)-L-cysteine-Dvaline synthetase (ACVS), a nonribosomal peptide synthetase or NRPS.

The second step in the biosynthesis of penicillin G is the oxidative conversion of linear ACV into the bicyclic intermediate isopenicillin N by isopenicillin N synthase (IPNS), which is encoded by the gene pcbC. Isopenicillin N is a very weak intermediate, because it does not show strong antibiotic activity. The final step is a transamidation by isopenicillin N Nacyltransferase, in which the aminoadipyl sidechain of isopenicillin N is removed and exchanged for a phenylacetyl side-chain. This reaction is encoded by the gene penDE, which is unique in the process of obtaining penicillins.

1.6. The commercial production of penicillin (Fermentation)

The fermentation production of penicillin-G or -V is a fed-batch process carried out aseptically in stainless steel tank reactors of 30,000100,000 gallon capacity. The fermentation usually involves two to three initial seed growth phases followed by a

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Project Pneumonia (Chemistry)

fermentation production phase having a time cycle ranging from 120 to 200 h. High dissolved oxygen levels are critical, especially during peak growth periods that often occur at the 4050 h time-period of the cycle. The fermentation mode is fed-batch and crude sugar and precursor are fed throughout the cycle. Current penicillin fermentations are highly computerized and automated. Temperature, pH, dissolved oxygen, carbon dioxide, sugar, precursor, ammonia, etc. are closely monitored and controlled for optimal antibi-otic production (Waites et al. 2001). Various carbon sources have been adopted for the fermentation including glucose, sucrose and other crude sugars. About 65% of the carbon is metabolized for cellular maintenance, 2025% for growth and 1012% for penicillin production (Van Nistelrooij et al. 1998). Sugar and precursor are fed continuously and the sugar is also used to help regulate the pH of the fermentation to between 6.46.8 during the active penicillin production phase. Corn steep liquor and cottonseed or soybean meal, ammonia and ammonium sulfate represent major nitrogen sources. The essential precursor substances are phenyl-acetic acid (for penicillin G) or phenoxyacetic acid (for penicillin V) that are either fed or batched. Penicillin is excreted into the medium and is recovered at the end of the fermentation. Whole broth extraction is usually performed at acidic pH by most manufacturers and has resulted in a 25% improvement in overall extraction efficiency by the elimination of the rotary vacuum filtration step. Solvent extraction of chilled acidified broth is carried out with amyl, butyl or isobutyl acetate. Multiple back-extractions into buffer and solvent at varying pH using countercurrent contactors has led to considerable penicillin concentration in the early recovery stages of the purification process. Pigments and other broth impurities are removed by the use of activated charcoal. The penicillin is crystallized upon the addition.

1.7

Sheehans synthesis (Penicillin V Sheehans original Paper is attached to the report)

Before the invention of this reaction, it was known that numerous lactonization procedures for ring formation had been tested and had proved too harsh. There was a

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need for a mild late-state ring formation. Sheehans group had been investigating the formation of a amide linkages under neutral aqueous conditions via the treatment of carboxylic acid with an amine in the presence of DCC (N,N-dicyclocarbodiimide).

1.8. Aminopenicillins
The aminopenicillins (sometimes referred to as third-generation penicillins) are semisynthetic modifications of natural penicillin that have the advantage of a broader spectrum of activity. Like the natural penicillins, aminopenicillins have a thiazolidine ring structure connected to a beta-lactam ring which makes these agents susceptible to inactivation by beta-lactamase, the usual cause of bacterial resistance to the penicillins. The aminopenicillins like the natural, first-generation penicillins (Penicillin) bind to bacterial proteins and inhibit synthesis of the bacterial cell wall, causing cell lysis particularly in rapidly growing organisms. Two third-generation penicillins are available in the United States: ampicillin and amoxicillin. Amoxicillin is commonly used in combination with the beta-lactamase inhibitor clavulanic acid. Amoxicillin/clavulanate (Augmentin which will be discussed ahead) is one of the most frequent causes of drug-induced liver disease(A side effect of Clavulanate), but the liver injury is probably due to the clavulanate rather than the aminopenicillin.

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Amoxicillin (INN), formerly amoxycillin (BAN), and abbreviated amox, is a moderatespectrum, bacteriolytic, -lactam antibiotic used to treat bacterial infections caused by susceptible microorganisms. It is usually the drug of choice within the class because it is better absorbed, following oral administration, than other -lactam antibiotics. Amoxicillin is one of the most common antibiotics prescribed for children. The drug became available in 1972. Amoxicillin is susceptible to degradation by -lactamase-producing bacteria, which are resistant to a broad spectrum of -lactam antibiotics, such as penicillin. For this reason, it is often combined with clavulanic acid, a -lactamase inhibitor. This increases effectiveness by reducing its susceptibility to -lactamase resistance and that is the main reason we have decided to include the drug Augmentin (Amoxicillin/Clavulanate) in this report.

1.9. History of Amoxicillin

Amoxicillin was discovered by scientists at Beecham Research Laboratories in 1972. In the US it is marketed by GlaxoSmithKline (the inheritor company) under the original trade name Amoxil.The narrow spectrum of antimicrobial activity of the penicillins, led to the search for derivatives of penicillin which could treat a wider range of infections. The first important step forward was the development of ampicillin. Ampicillin had a broader spectrum of activity than either of the original penicillins and allowed doctors to treat a broader range of both Gram-positive and Gram-negative infections.Further developments led to amoxicillin, with improved duration of action. It differs structurally from ampicillin merely by having an additional hydroxyl group on the benzene ring.

1.10. Chemical structure

Amoxicillin (Trade name: Amoxil) IUPAC name: 2S,5R,6R)-6-{[(2R)-2-Amino-2-(4-hydroxyphenyl)acetyl]amino}-3,3dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid.

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Project Pneumonia (Chemistry)

Average molecular mass: 365.404205 Da (Dalton) Chemical Structure Fig. I Fig. II

Figure I is a two dimensional structure of Amoxicillin, while figure II is a three dimensional structure of the same. In the structure there are: 5 double bonds 46 bonds 5 bonds 1 Carboxyl group H-Bond Donor: 4 H-Bond Acceptor: 7 Total bonds (Not including possible H-Bonds) = 57.

1.11. Dosage of Amoxicillin

The dosage of Amoxicillin specifically for bacterial pneumonia is 500 mg orally 3 times a day or 875 mg orally twice a day may be administered for 7 to 10 days if pneumococcal pneumonia is suspected Only mild pneumonia due to pneumococcus should be treated with amoxicillin.

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1.12. Dosage of Penicillin V

I.M., I.V.: 100-150 mg/kg/day in divided doses every 6 hours (maximum: 2-4 g/day) Oral: 50-100 mg/kg/day in doses divided every 6 hours (maximum: 2-4 g/day).Severe infections/meningitis: I.M., I.V.: 200-400 mg/kg/day in divided doses every 6 hours (maximum: 6-12 g/day).Streptococcal infectionsmild to moderately severeof the upper respiratory tract: 125 to 250 mg (200,000 to 400,000 units) every 6 to 8 hours for 10 days.

1.13. Dosage of Penicillin G

Aqueous penicillin G -1 to 2 million units IV every 4 hours for 7 to 14 days, depending on the nature and severity of the infection.

1.14. Chemical Synthesis of Amoxicillin(Via Dane process) -I

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s 1.15. Chemical Synthesis of Amoxicillin (Grossman et al.)(Higher level) Via Silylation of 6-APA and TCMS (Trimethylchlorosilane)

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Project Pneumonia (Chemistry)

Silylation is the introduction of a (usually) substituted silyl group (R3Si) to a molecule.There is provided by the present invention, in the process for the production of amoxicillin trihydrate which comprises the consecutive steps of:

Silylating 6-aminopenicillanic acid, preferably with chlorotrimethylsilane (Highly flmmable) (TMCS) in an anhydrous solvent, preferably methylene chloride, in the presence of a strong base, preferably a tertiary aliphatic amine and especially triethylamine. Acylating the silylated 6-aminopenicillanic acid formed in the previous step with D-( - )-2-para-hydroxyphenylglycine chloride hydrochloride in the presence of a weak base, preferablydimethylaniline. Hydrolyzing and neutralizing the product of said acylation to produce amoxicillin trihydrate.

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1.16. Enzymatic synthesis of Amoxicillin (Via hydroxyphenylglycine methyl ester)

The enzymatic processes offer important advantages over these conventional processes and are becoming of greater relevance, since the reactions can be performed in a single step with high yield and specificity, under mild conditions, minimizing or eliminating waste and avoiding the use of toxic solvents. (Ospina et al., 1996; Diender et al., 1998, Hernndez-Jstiz et al., 1999; Wegman et al., 2001).

Among the enzymatic approaches, the kinetically controlled route shows feasibility for the synthesis of antibiotics derived from -amino acids (Youshko et al., 2000), which uses an activated side chain donor (e.g., an ester or amide) and the penicillin nucleus, 6aminopenicillanic acid (6-APA). In the enzymatic synthesis of amoxicillin from hydroxyphenylglycine methyl ester (HPGM) and 6-APA, as indicated in the figure, the Penicillin G Acylase (PGA) catalyzes both the synthesis of the antibiotic by coupling (Reaction 1) and the undesired hydrolysis of the substrate (Reaction 2) and its product (Reaction 3), generating hydroxyphenylglycine (HPG) and alcohol. Therefore, the yield of the process depends on the kinetic rates of these three reactions, where the antibiotic acts as the intermediate component within a set of series-parallel reactions (Santana et al., 2010). Thus, the concentration curve of antibiotic reaches a maximum value, beyond which the hydrolytic reactions prevail.

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This reaction could provide this project a totally different outlook to this - The kinetics involved in parallel reaction. The shifting of equilibrium is essential to increase the yield. Thus, other than just organic chemistry we could have included chemical kinetics and chemical equilibrium, but due to the constraints of the guidelines in the project- we have not done this in detail. Since the enzymatic reaction occurs in the liquid phase, a way to shift the equilibrium towards the synthesis of amoxicillin is by decreasing its concentration in the aqueous medium by reducing its solubility. This can be performed by changing the conditions of pH, temperature and ethanol composition. Thus, the antibiotic in excess in relation to its solubility will be transferred to the solid phase by crystallization and will not be available for hydrolysis, increasing significantly the productivity and selectivity of the process. Solid-liquid equilibrium data, or solubility measurements, are therefore an important tool for the description of the behavior of the compounds involved in the enzymatic synthesis of amoxicillin, since solid and liquid equilibrium is the basis for separation processes, e.g., crystallization.

1.17. - Lactam antibiotics(Both Penicillin and Amoxicillin belong to this class)

-Lactam antibiotics (beta-lactam antibiotics) are a broad class of antibiotics, consisting of all antibiotic agents that contains a -lactam ring in their molecular structures. This includes penicillin derivatives (penams), cephalosporins (cephems), monobactams, and carbapenems. Most -lactam antibiotics work by inhibiting cell wall biosynthesis in the bacterial organism and are the most widely used group of antibiotics. Up until 2003, when measured by sales, more than half of all commercially available antibiotics in use were -lactam compounds. Bacteria often develop resistance to -lactam antibiotics by synthesizing a -lactamase, an enzyme that attacks the -lactam ring. To overcome this resistance, -lactam antibiotics are often given with -lactamase inhibitors such as clavulanic acid. (When Amoxicillin is given the -lactamase inhibitor, Clavulanic acid/Clavulanate it is is called Augmentin and the next topic will be about this drug.

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1.18. Mechanism of action of -lactam antibiotics

-Lactam antibiotics are bactericidal, and act by inhibiting the synthesis of the peptidoglycan layer of bacterial cell walls. The peptidoglycan layer is important for cell wall structural integrity, especially in Gram-positive organisms, being the outermost and primary component of the wall. The final transpeptidation step in the synthesis of the peptidoglycan is facilitated by DDtranspeptidases which are penicillinbinding proteins (PBPs). PBPs vary in their affinity for binding penicillin or other -lactam antibiotics. The amount of PBPs varies among bacterial species. -Lactam antibiotics are analogues of d-alanyl-d-alanine(This is one theory to explain the mechanism)the terminal amino acid residues on the precursor NAM/NAG-peptide subunits of the nascent peptidoglycan layer. The structural similarity between -lactam antibiotics and d-alanyl-d-alanine facilitates their binding to the active site of PBPs. The -lactam nucleus of the molecule irreversibly binds to the PBP active site. This irreversible inhibition of the PBPs prevents the final crosslinking (transpeptidation) of the nascent peptidoglycan layer, disrupting cell wall synthesis. Under normal circumstances, peptidoglycan precursors signal a reorganisation of the bacterial cell wall and, as a consequence, trigger the activation of autolytic cell wall hydrolases. Inhibition of cross-linkage by -lactams causes a build-up of peptidoglycan precursors, which triggers the digestion of existing peptidoglycan by autolytic hydrolases without the production of new peptidoglycan. As a result, the bactericidal action of lactam antibiotics is further enhanced.

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1.19. Potency of - Lactam Antibiotics

Two structural features of -lactam antibiotics have been correlated with their antibiotic potency. The first is known as "Woodward's parameter", h, and is the height (in angstroms) of the pyramid formed by the nitrogen atom of the -lactam as the apex and the three adjacent carbon atoms as the base. The second is called "Cohen's parameter", c, and is the distance between the carbon atom of the carboxylate and the oxygen atom of the -lactam carbonyl. This distance is thought to correspond to the distance between the carboxylate-binding site and the oxyanion hole of the PBP enzyme. The best antibiotics are those with higher h values (more reactive to hydrolysis) and lower c values (better binding to PBPs).

1.20. Resistance to - Lactam Antibiotics

By definition, all -lactam antibiotics have a -lactam ring in their structure. The effectiveness of these antibiotics relies on their ability to reach the PBP intact and their ability to bind to the PBP. Hence, there are two main modes of bacterial resistance to lactams: Enzymatic hydrolysis of the -lactam ring (by penicillinase or -lactamase): If the bacterium produces the enzyme -lactamase or the enzyme penicillinase, the enzyme will hydrolyse the -lactam ring of the antibiotic, rendering the antibiotic ineffective. The genes encoding these enzymes may be inherently present on the bacterial chromosome or may be acquired via plasmid transfer (plasmid mediated resistance), and -lactamase gene expression may be induced by exposure to lactams, which is the main reason that resistance may develop. Possession of altered penicillin-binding proteins: As a response to increased efficacy of -lactams, some bacteria have changed the proteins to which -lactam antibiotics bind. -Lactams cannot bind as effectively to these altered PBPs, and, as a result, the -lactams are less effective at disrupting cell wall synthesis. Notable examples of this mode of resistance include methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-resistant Streptococcus pneumoniae. Altered PBPs do not necessarily rule out all treatment options with -lactam antibiotics. The production of a -lactamase by a bacterium does not necessarily rule out all treatment options with -lactam antibiotics. In some instances, -lactam antibiotics may be co-administered with a -lactamase inhibitor, an example is Clavulanate/Clavulanic Acid and that is the purpose of our next topic.

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1.21. Augmentin (Trade name by GlaxoSmithKline)(Amoxicillin/clavulanic acid (INN))

The combination was invented around 1977/78 by British scientists working at Beecham (now part of GlaxoSmithKline), which filed for US patent protection for the drug combination in 1979. A patent was granted in 1984. Augmentin is the original name used by its inventor.Clavulanate was added to amoxicillin to give the combination drug greater activity against those organisms that produce non-group 1 (class A) -lactamases. The mechanisms of action of amoxicillin/clavulanate are interference with cell wall synthesis by attachment to penicillin-binding proteins (PBPs), inhibition of cell wall peptidoglycan synthesis and inactivation of inhibitors to autolytic enzymes. Amoxicillin and its clavulanate combination can be administered orally. Augmentin acts on bacteria that produce beta-lactamase, including S. aureus, E. coli, H. influenzae, K. pneumomiae.

Quality control

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Reflections
Saurav Kini (Team leader)
Before we started this research project, I did not know much about the topic except that penicillin equals Alexander Fleming. A few other things that I thought about the topic were that it would be an extremely long paper and that we would have to spend a lot of time working on it. Well, I was right! In the process of this project I have learnt a ton. This was one of the first experiences of working as a close team in which work was roughly evenly divided. One of the most prominent ideas I had from the day I found that we would not be able to make this drug in a laboratory or rather in our laboratory was that we would use the software Camtasia studio 8 for making our movie instead of using the traditional movie make Because it was too mainstream. Over the course of two weeks I have observed that we started to work more efficiently and even due to a few fights we stuck to the schedule, I know for myself, that I have tried to meet whenever I was free and that I have tried not to boss around. The Chemistry involved in this project (ex. Sheehans process ) was way above my level. It took an extra effort just to understand a part of John C.Sheehans paper and it was a challenge to derive conclusions from other synthesis too. Looking at the header of John C.Sheehans paper Contribution from the Department of Chemistry, Massachusetts Institute of Technology was one of the most inspiring moments in this project. The fact that I could understand his paper to an extent inspired me quite a bit. The level of IUPAC nomenclature was also a challenge, some of it indeed went over my head!. Well, at the end of this research paper, I can easily conclude that it was fruitful and definitely not a waste of time- in other words I can guarantee that I would never have come to know about compounds such as DCC and HPGE without this project. Relating the chemistry we have studied to learning how to read a higher level research paper was another thing that I learnt. I encountered various alternate interpretations mainly of the various syntheses for a drug. A huge thing that I learnt was that when chemical mechanisms come into play, each scientist has an own one! Although I could not make a lot of connections with was I am currently learning, my basics of organic chemistry and the chemical kinetics chapter that I am currently learning also helped (ex. Parallel reactions). To conclude this reflection, I seriously think that I should improve our time management skills, and for our next immediate projects .i.e., the Biology and Physics part of this

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project I should take more initiative in gathering the group and making the our discussions for effective.

Bij Javia
This is my first research based project. The project required us to explain what is pneumonia, how it is spread, how the disease is established in human body, how it is diagnosed, working of instruments used in diagnosis, drugs used, development of those drugs, their mode of action and an effort to spread awareness about pneumonia. This project is about the chemistry aspect which includes drugs and their development in the laboratories as well as large scale commercial production andtheir mode of action. From all of the above mentioned topics that were supposed to be covered I did not have a slightest clue about any of them except that I had a general idea about what is pneumonia. The topics were thought provoking and stimulated the minds to ask those questions that I had never asked and had been completely oblivious such things. The sheer number of tasks on our plate left confused about where to begin from. However as we visited quite a few hospitals, and took on extensive researching and surfing net I saw a vast amount of information out there for us. I realized our only task was to get the information in a systematic order and present it in a creative way. For that we decided to make our own website and then featuring it in our video. To do that one of my team mates, Saurav found a movie making software, camtasia studio 8. And then it looked pretty simple. But it was not so. There was so much of information and some of the methods of synthesis were quite complex. However with a little patience and continued efforts we had the website ready. Then we simply made a power point presentation explaining all those topics that could not be included in the movie and the others in brief. Using the Camtasia studio we filmed the website and the project was nicely done. Previously I had very scarce knowledge of pneumonia and even the general action of antibiotics. I had never pondered how at molecular level the medicines would be affecting our body chemistry. The simplicity of the the way the penicillin forms a single covalent bond and irreversibly inhibits an enzyme which would cause a death of bacteria is awe inspiring. It was fun and an eye opening experiences to see how the complexities of life are reduced by a simple yet extremely efficient solution. Mans task on earth is simply to unravel the working of nature and gain its understanding to find solutions to all his problems.

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2013, 2014 by Saurav Kini, Bij Javia and Khyati Kansagra

Project Pneumonia (Chemistry)

Khyati Kansagra For the first time ever, I worked on such a project, where all the three subjects were combined in a single project. I loved working on this project as it covered all the aspects of the topic. It was fun visiting hospitals and gathering information about our topic Pneumonia Priorly, I just knew pneumonia as a disease related to lungs and some of its symptoms. But towards the end of this project, I am well aware about different types of pneumonia, its symptoms on each age group, the drugs which are used for treatment of it, i.e Lactam antibiotics: Penicillin V, Penicillin G, Amoxicillin and augmentin. We also learned about the machines used for the treatment, most important being X-rays, as Pneumonia is a X-ray diagnosed disease. Towards the end of the project, we were surely exhausted as we (Bij, Saurav and me) all put in tremendous efforts to make the report, presentations and movie. Undoubtedly, there were many contradictory thoughts, ideas and plans but we did make it a success. Working in group, giving time for the project, meeting at each others places has made us even more good friends and the team work quality of each one of us is improved. We learnt to adjust to others schedule and find the time to complete this project. It was a great learning experience. The only major problem we faced was time management, as everytime we all three had clash in our schedules. Other problem we faced was gathering statistics of Pneumonia as it is X-ray diagnosed disease and it is also not listed under infectious disease so they dont keep record of pneumonia. I feel that if we had got more time to submit the project we would have had done although more good and effective work. Khyati kansagra

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2013, 2014 by Saurav Kini, Bij Javia and Khyati Kansagra