INTRODUCTION:

The term chemotherapy can be defined as 'the treatment of diseases caused due infective parasites or organisms without causing destruction of their animal host'. Modi chemotherapy began with the work of Paul Ehrlich (1854 1915). Due to his pion discoveries in this field, he is regarded as "Father of Chemotherapy"¹. The second phase of revolution emerged in the 1930's (following the discovery of 1 British bacteriologist Alexander Fleming when he tested the filtrate of a broth culture of penicillium mold for its antibacterial activity. The term antibiotic has its origin in the word antibiosis (ie, against life); the latter bei first time used by Vuillemin in 1889 in an attempt to describe the concept of survival of 1 fittest.

Although the discovery of penicillin is named after Sir Fleming in 1928, it was not ur 1940 at Oxford that Florey and Chain and their associates isolated it and described properties in detail, and thus turning Fleming's discovery to practical significance. Among the many attempts to define the term antibiotic, the most appropriate one m be stated as "An antibiotic is a chemical compound derived from or metabolically produc by microorganism and that in high dilution antagonizes the growth and/or the survival one or more species of microorganisms"². The probable points of differences amongst t antibiotics may be physical, chemical and pharmacological properties, antibacterial spect and mechanism of action.³

What are antibiotics:

Any substance that inhibits the growth and replication of a bacterium or kills it outright can be called an antibiotic. Antibiotics are a type of antimicrobial designed to target bacterial infections within the body. This makes antibiotics subtly different from the other main kinds of antimicrobials widely used today:

Antiseptics are used to sterilise surfaces of living tissue when the risk of infection is high, such as during surgery.⁴

Disinfectants are non-selective antimicrobials, killing a wide range of micro-organisms including bacteria. They are used on non-living surfaces, for example in hospitals. Of course, bacteria are not the only microbes that can be harmful to us. Fungi and viruses can also be a danger to humans, and they are targeted by antifungals and antivirals, respectively. Only substances that target bacteria are called antibiotics, while the name antimicrobial is an umbrella term foranything that inhibits or kills microbial cells including antibiotics, antifungals, antivirals and chemicals such as antiseptics.⁵

Most antibiotics used today are produced in laboratories, but they are often based on compounds scientists have found in nature. Some microbes, for example, produce substances specifically to kill other nearby bacteria in order to gain an advantage when competing for food, water or other limited resources. However, some microbes only produce antibiotics in the laboratory.⁶

History of antibiotics:

Antibiotics have been used for millennia to treat infections, although until the last century or so people did not know the infections were caused by bacteria. Various moulds and plant extracts were used to treat infections by some of the earliest civilisations – the ancient Egyptians, for example, applied mouldy bread1 to infected wounds. Nevertheless, until the 20^th century, infections that we now consider straightforward to treat – such as pneumonia and diarrhoea – that are caused by bacteria, were the number one cause of human death in the developed world 2,3,4. It wasn’t until the late 19th century that scientists began to observe antibacterial chemicals in action.⁷ Paul Ehrlich, a German physician, noted that certain chemical dyes coloured some bacterial cells but not others5He concluded that, according to this principle, it must be possible to create substances that can kill certain bacteria selectively without harming other cells. In 1909, he discovered that a chemical called arsphenamine was an effective treatment for syphilis. This became the first modern antibiotic, although Ehrlich himself referred to his discovery as ‘chemotherapy’ – the use of a chemical to treat a disease6. The word ‘antibiotics’ was first used over 30 years later by the Ukrainian-American inventor and microbiologist Selman Waksman, who in his lifetime discovered over 20 antibiotics.⁸

Why are antibiotics important:

The introduction of antibiotics into medicine revolutionised the way infectious diseases were treated. Between 1945 and 1972, average human life expectancy jumped by eight years, with antibiotics used to treat infections that were previously likely to kill patients. Today, antibiotics are one of the most common classes of drugs used in medicine and make possible many of the complex surgeries that have become routine around the world. The public health revolution that antibiotics brought about was not without its cost. The more we use them, the more resistant bacteria become.⁹ The US Department of Health estimates that half of all antibiotics used worldwide are either unnecessary or prescribed incorrectly8.With antibiotic resistance on the rise, increasing numbers of people die every year of infections caused by bacteria that have become resistant to the antibiotics previously used to treat them. It is estimated that, by 2050, the global cumulative cost of antibiotic resistance will reach US$100 trillion9. In the 1950s and 1960s new drugs were being isolated all the time 10, 11. However, the rate of drug discovery has slowed markedly. This lack of effective new antibiotics means that drugs previously set aside as ‘reserve’ antibiotics, meant to be used only when no other treatment is available are being used more and more regularly – and resistance is developing to them, too. Some of these reserve antibiotics are also more toxic or have more severe side effects than more standard antibiotic treatments.^10,11

Routes of administration:

There are many different routes of administration for antibiotic treatment. Antibiotics are usually taken by mouth. In more severe cases, particularly deep-seated systemic infections, antibiotics can be given intravenously or by injection. Where the site of infection is easily accessed, antibiotics may be given topically in the form of eye drops onto the conjunctiva for conjunctivitis or ear drops for ear infections and acute cases of swimmer's ear¹². Topical use is also one of the treatment options for some skin conditions including acne and cellulitis. Advantages of topical application include achieving high and sustained concentration of antibiotic at the site of infection; reducing the potential for systemic absorption and toxicity, and total volumes of antibiotic required are reduced, thereby also reducing the risk of antibiotic misuse¹³. Topical antibiotics applied over certain types of surgical wounds have been reported to reduce the risk of surgical site infections. However, there are certain general causes for concern with topical administration of antibiotics. Some systemic absorption of the antibiotic may occur; the quantity of antibiotic applied is difficult to accurately dose, and there is also the possibility of local hypersensitivity reactions or contact dermatitis occurring. It is recommended to administer antibiotics as soon as possible, especially in life-threatening infections. Many emergency departments stock antibiotics for this purpose.¹⁴

How do antibiotics work:

Antibiotics are used to treat bacterial infections. Some are highly specialised and are only effective against certain bacteria. Others, known as broad-spectrum antibiotics, attack a wide range of bacteria, including ones that are beneficial to us. There are two main ways in which antibiotics target bacteria. They either prevent the reproduction of bacteria or they kill the bacteria, for example by stopping the mechanism responsible for building their cell walls.¹⁵

CLASSIFICATION:

1. Depending upon clinical effectiveness, spectrum of activity and degree of selectivity, those inhibiting only one group of microorganism are called as 'narrow spectrum antibiotics. nystatin and bacitracin. These antibiotics exhibit a high degree of selectivity. A few antibiotics inhibit both gram-positive and gram-negative bacteria and/or other intracellular organism may be termed as broad-spectrum antibiotics eg. chloramphenicol and stracyclines.¹⁶

2. Depending upon the sources from which antibiotics are obtained they can be classified as follows:

a. Natural: These antibiotics are obtained from the large scale fermentation of microorganisms. e.g. bacitracin and polymixin are obtained from some bacilli while streptomycin, tetracyclines etc. from streptomyces species.

b. Semisynthetic: The observation that 6-aminopenicillanic acid can be obtained from cultures of P. chrysogenum that were depleted of side chain precursors led to the development of this class¹⁷. For example, during the commercial production of benzyl penicillin (Penicillin G), phenylacetic acid is added to the medium in order to achieve predominance of the product.

c. Synthetic: This class includes antibiotics which are having purely synthetic origin. For example, Chloramphenicol, a broad spectrum antibiotic initially isolated from a fermented media in 1947 and later was produced synthetically on a commercial basis.

3. The third basis of classification involves the differences in mechanism of action. Accordingly these agents can be divided as:

a. Drugs that interfere with the biosynthesis of bacterial cell-wall eg. Penicillins, O Cephalosporins, Cycloserine, Bacitracin and Vancomycin.

b. Drugs that interfere in the functioning of cytoplasmic membrane e.g. Polymixins. Amphotericin B and Nystatin.

c. Drugs that interfere with the protein biosynthesis eg. Erythromycin, Lincomycins, Tetracyclines, and Chloramphenicol and

d. Drugs that interfere with the nucleic acid biosynthesis eg. Actinomycin, Griseofulvin and Rifampin.

4. Antibiotics can be in general classified as (A) B-lactam antibiotics (C) Tetracycline antibiotics (E) Macrolide antibiotics (G) Unclassified antibiotics (B) Aminoglycoside antibiotics. (D) Peptide antibiotics (F) Lincomycins¹⁸

B-LACTAM ANTIBIOTICS:

1. Penicillins:

Even though penicillin had been discovered in 1928, and is a member of B-lact antibiotics, the term B-lactam antibiotics had to wait till 1942 to get registered in dictionary of medicinal chemists. Thanks to Prof. Howard W. Florey and Dr. Ernst B. Ch working at that time at the William Dunn School of Pathology. Oxford with their sinc efforts, isolated and characterised the basic structure of the penicillins. This work supplemented by the efforts of the chemists Dr. Abraham and Dr. Heatley. The clin effectiveness of penicillin was first tested on 12 February, 1941 in the form of a sodium sa Thus, long after the antibiotic projected its appearance on the screen of research, structure of penicillin was determined. H R-C-NH-C CH C CH₂ CH₂ CH-COOH Penicillins The penicillins can be considered as the amido derivatives of the 6-aminopenicill H acid.¹⁹ HN Ở CH N CH₂ A CH₂ CH-COOH 6-Aminopenicillanic acid (6-APA) In the basic skeleton, a thiazolidine ring (A) is fused with a beta-lactam ring (B) which four membered cyclic amide. The penicillins differ from each other in antibacterial. pharmacological characteristics due to variation in the structure of acid moiety of the am side-chain at C-6. For example, penicillin G (where, R CH, CH,-) after about 45 year clinical use, remains an extremely effective and is the only natural penicillin used clinic Acylation of 6-APA with appropriate carboxylic acids resulted in new penicillins, some which are broad-spectrum antibiotics.²⁰ Degradation Products of Penicillins: Natural penicillins are acid and base unstable. Instability in acid media logic precludes their oral administration due to the highly acidic pH in stomach. At acidic pl sort of molecular rearrangement results. The compound is known as penillic acid and has activity. Similarly at basic pH, penicillin molecule gets converted to penicilloic acid which again an inactive form. Certain strains of microorganisms can destroy beta-lactam antibiotics enzymatically. enzymes are more popularly known as penicillinases or B-lactamases can open the B-lad bond. The difference in the susceptibility to the B-lactamase enzymes depends upon nature of the amide side-chain at C-6. It also depends upon the bacterial strain involved.²¹

SAR of B-lactam Antibiotics:

Antibiotic All B-lactam antibiotics contain a four membered B-lactam ring which is fused through the nitrogen and tetrahedral carbon atom to a second heterocyclic ring. Difference in tl structure of this second heterocyclic ring leads to sub-divisions of B-lactam antibiotics. For example, (A) Penicillins consist of ß-lactam ring fused with thiazolidine. (B) Thienamycins consist of ß-lactam fused with pyrroline ring. (C) Clavulanic acid consists of ß-lactam fused with oxazolidine ring and (D) Cephalosporines consist of B-lactam fused with a six membered dihydrothiazir ring. A carbonyl group attached to the lactam nitrogen is a common feature of all abo classes. Since, penicillin after its clinical application in second world war proved to be a wound drug in healing the wounds and preventing the infections, extensive chemical studies were undertaken either individually or through co-operation of both, industrial as well government laboratories. Soon after, the scientists seemed disappointed due to relative instability of natural penicillin in acidic or basic medium. For example, benzyl penicillin we found to be a relatively narrow spectrum antibiotic.²² It is susceptible to degradation under acidic or basic conditions, certain strains of microorganisms carry ß lactamase enzymes tha inactivate the drug by hydrolysis, and many patients may allergic to it. Many analogues ha been synthesized in order to overcome these clinical deficiencies prevailing in natura penicillins. The main principles behind this drug design was the manipulation of polar amid side-chains. Variations in this moiety resulted in differences in antibiotic potency and i chemical-physical properties including stability. Introducing chemical inducers in the culture medium by varying the nutrition composition of the growth medium, by including mutational change in the strain c microorganism are but few tools employed to increase both quality and quantity c antibiotics. e.g.

1. 6-Aminopenicillanic acid is produced in large quantities with the aid of a amidase from Penicillium chrysogenum and the culture medium is fed with the chemica inducers (eg. Phenylacetic acid) in order to achieve the predominance of the desirer antibiotic.

2. The stability of benzyl penicillin can further be increased by substitution of ar electron withdrawing group at a-position of benzyl penicillin. e.g. the a-aminobenzyl a-halobenzyl and phenoxy-methylpenicillin are significantly more benzylpenicillin towards acid catalysed hydrolysis. stable thar

3. Some bacteria, for example, many species of gram negative bacilli are naturally resistant to the action of penicillins. Other normally sensitive species are capable of developing penicillin resistance.²³

HYPERSENSITIVITY OR ALLERGIC REACTIONS:

Hypersensitivity reactions may occur with any dosage form of penicillin. In some cases, the reaction is mild and disappears even while the use of drug is continued. While in others, reactions may persist for 1 or 2 weeks or longer after therapy has been stopped. These reactions include immediate or delayed type skin allergies, fever, bronchospasm, serum sickness and anaphylactic reactions. These manifestations may be due to the following reasons.²⁴ (a) A breakdown product, penicilloyl moiety results due to opening of B-lactam ring. This fraction is considered to be the most important antigenic intermediate of penicillins. (b) Certain other contaminants (mycelial residues) of high molecular weight originating from fermentation process may serve as a cause of manifestations. (c) A non-protein polymer of unknown origin may also be present in penicillin and may be antigenic. (d) The degradation products, penicillanic acid and/or penicilloate may interact with sulfhydryl/amino groups present in vital tissue proteins. The resulting complexes may serve themselves as penicillin antigens. Thus above mentioned reactions are responsible for releasing foreign proteins in the body which ultimately leads to the generation of allergic reactions to penicillins.²⁵

CEPHALOSPORINS:

The concept that certain antibiotic producing fungi may occur in soils and further environments rich in bacteria led to a worldwide examination of soils, sewage sludges and related material for new antibiotic. The concept crystallised out with some signal successes²⁶. A species of Cephalosporium, isolated near a sewage outfall of the Sardinian coast by Brotzu in 1948 was studied at Oxford. The mould produced three antibiotics which were named as:

1. Cephalosporin N: It has a penicillin like structure being a derivative of 6-aminopenicillanic acid.

2. Cephalosporin P: An acidic antibiotic, which is steroidal in nature.

3. Cephalosporin C: It is a true cephalosporin and is a derivative of 7 amino - cephalosporanic acid. The latter served as a lead nucleus for the development of totally new series of compounds, Cephalosporins.²⁷

TETRACYCLINE ANTIBIOTICS:

A clear cut division of work is observed amongst previous two classes of antibiotics penicillins being active against gram-positive organisms while Streptomycin family being incharge of gram-negative affairs. Generation of the tetracyclines was the result of a need to develop such antibiotics which can effectively cover both microbial faculties.²⁸ The series consists of about eight members: 7-chlortetracycline discovered in 1948 by Duggar. They are obtained either as metabolic by-product from various species of Streptomyces or as semisynthetic derivatives of the natural products. Tetracyclines are all yellow amphoteric compounds forming salts with either acids or bases. They exist as zwitter ions at pH 7. Although they are not completely absorbed from GIT, tetracyclines are known for their oral use.²⁹ Exception is rolitetracycline which is given parenterally. Epimerization at C-4 is witnessed with tetracyclines in the solutions of intermediate pH range. Epitetracyclines, as these isomers are known by, exhibit much less activity than the neutral isomers. Resistance to the tetracyclines develops relatively slowly, cross-resistance (ie. an organism resistant to one drug shows resistance to all other members of the series) is also reported. Most of the members safely escape the metabolic degradation after absorption but chlortetracycline and doxycycline do not exhibit this tendency.³⁰

Side Effect of Antibiotics:

Antibiotics may have side effects. Some of the more common side effects may include:

· Soft stools or diarrhea

· Mild stomach upset

· Vomiting

· Severe watery diarrhea and abdominal cramps

· Allergic reaction (shortness of breath, hives, swelling of lips, face, or tongue, fainting)

· Rash

· Vaginal itching or discharge

· White patches on the tongue³¹

What Are Symptoms of an Allergic Reaction to an Antibiotic:

Some people are allergic to certain types of antibiotics, most commonly penicillin. If you have a question about a potential allergy, ask your doctor or pharmacist before taking the medicine.^32,33

Allergic reactions commonly have the following symptoms:

· Shortness of breath

· Rash

· Hives

· Itching

· Swelling of the lips, face, or tongue

· Fainting

CONCLUSION:

In conclusion, antibiotics can also have adverse effects on your health in the long run. In fact, it has already been proven that a person who is on antibiotics for a prolonged period of time is more prone to developing infections and allergies. It is also important that you choose the right kind of antibiotic depending on your health condition. You must know what you really need and how you can take advantage of antibiotics’ power so that you can achieve better health. In order to prevent any side effects from occurring, you should have an understanding of the different kinds of bacteria that cause infections. Once you are aware of these, then you should be able to identify whether you really need to use antibiotics. Some bacteria types produce toxins that can weaken your immune system. You should also know that antibiotics work by killing bacteria and suppressing their functions such as metabolism and digestion. This means that if you suppress bacteria, then you will also suppress other helpful bacteria in your body.

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Received on 30.10.2021 Modified on 11.11.2021

Asian J. Research Chem. 2022; 15(1):91-96.

DOI: 10.52711/0974-4150.2022.00015