antimicrobial agents and antibacterial antibiotics: …

www.wjpps.com Vol 9, Issue 7, 2020.

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Sheela et al. World Journal of Pharmacy and Pharmaceutical Sciences

ANTIMICROBIAL AGENTS AND ANTIBACTERIAL ANTIBIOTICS:

AN OVERVIEW

Thorat Sheela Shivaji*, Mali Ramling Dnyaneshwar, Inamdar Nassruddin Rafik and

Upadhye Shashikant Sudarshan

Department of Pharmaceutical Chemistry, Annasaheb Dange College of B. Pharmacy, Ashta.

Department of Pharmaceutics, Annasaheb Dange College of B. Pharmacy, Ashta. Anand

Colony, Ashta, Maharashtra 416301.

ABSTRACT

The bacteria were first identified by the scientist Van Leeuwenhoek.

Bacteria are simple celled microorganism; it consists of the cell wall,

cell membrane. Thus, the cell wall is made up of peptidoglycan. There

are two types of bacteria, gram-positive and gram-negative bacteria.

The antibiotics are the chemotherapeutic agents which are effective

against the bacterial infection. Furthermore, The antimicrobial agents

are the drugs which are responsible for killing and inhibiting the

growth of microorganism. The antibacterial antibiotics constitute the

Tetracycline, quinolone antibacterial, beta-lactam antibiotics has

classed such as penicillin, cephalosporin. This comprehensive study of

antibacterial antibiotics includes classification, History, nomenclature, chemical name,

mechanism of action, structural activity relationship, Pharmacokinetics, uses, side effect,

toxicities of penicillin, cephalosporin, tetracycline, quinolone antibacterial agents,

glycopeptide antibiotics.

KEYWORDS: Antibacterial antibiotics, Penicillin, Cephalosporin, Tetracycline, Quinolone,

glycopeptide antibiotic

INTRODUCTION

Bacteria are simple single celled micro-organism and it was first identified by the scientist

Van Leeuwenhoek in the year of 1670s.[30]

Later in nineteenth century, it was observed that

there is correlation between bacteria and disease.

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

SJIF Impact Factor 7.632

Volume 9, Issue 7, 839-867 Review Article ISSN 2278 – 4357

Article Received on

04 May 2020,

Revised on 24 May 2020,

Accepted on 14 June 2020

DOI: 10.20959/wjpps20207-16503

*Corresponding Author

Thorat Sheela Shivaji

Department of

Pharmaceutical Chemistry,

Annasaheb Dange College of

B. Pharmacy, Ashta.


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For proper selection of the antimicrobial it requires optimum knowledge of the

microbiological and pharmacological factors. Antimicrobial agents or antibiotics have three

important uses such as empirical, prophylactic, definitive therapy. In empirical therapy, the

antibiotics used in treatment of bacterial infection but it is used in combination therapy or

single broad spectrum antibiotics may be employed because, infection causing

microorganism have been not identified. Hence it is important to identify infecting

microorganism. Once the infecting microorganism identified the narrow spectrum antibiotics

used for completion of course or completion of dose. Narrow spectrum antibiotics have low

toxicity. Actually, antibiotics are potentially very toxic, but they are used if the infection is

severe or if the disease of severe type. The antibiotics are usually produces resistance to the

microorganism.[1,2]

History

The French scientist Pasteur was performed one elegant experiment which was related to

microorganism. From experiment it was demonstrated that some specific bacteria were

crucial to fermentation and some of them were widely spread over the area. From experiment

he concluded that, some of these bacteria might be responsible for spread of disease.

The famous surgeon Edinburgh Lister which was also known as advocate of Germ theory of

disease. the suggestion was given to him by their colleague, they told him, he infecting their

own patient, so Lister introduced or developed new drug carbolic acid as an antiseptic for the

sterilization of operation theatres, warts. Finally it was observed that, there is improvement in

survival of patients.[3]

The scientist Paul Enrlich was known as father of Chemotherapy. He spent his time and

career in study of the Immunochemistry and histology. He won Nobel prize for the

contribution of the study. In 1904, he switched and entered in field of chemotherapy. He

states the principle of chemotherapy. A chemical could or might interfere with proliferation

of microorganism at a concentration with tolerating its host. In 1910, Enrlich had successfully

synthesized or introduced a new synthetic drug, arsenic containing compound- Salvarsan,

although it was ineffective against protozoal infection such as Trypanosomia and sexually

transmitted disease such as syphilis. He has been proven that, this drug may be effective

against protozoa infection and syphilis.

The drug was used until it was replaced by penicillin antibiotics.


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Classification of Antimicrobial agents[7]

1. Based on chemical structure

Sulfonamide and related drugs: e. g. Sulfonamide, sulfadoxine, sulfamethoxazole,

Para-amino salicylic acid, Dapson.

Quinolone: Nalidixic acid, Norfloxacin, Ciprofloxacin, Sparfloxacin.

Beta-Lactam antibiotics: Penicillin, Cephalosporin, Monobactam, Carbapenam.

Macrolide antibiotics: Erythromycin, Azithromycin, Clarithromycin

Tetracycline : Oxytetracyclin, Doxycycline

Nitrobenzene derivative: Chloramphenicol

Lincosamide antibiotics: Lincomycin, clindamycin.

Polypeptide antibiotics: Polymixin, Bacitracin.

Oxazolidinone: Linezolid

Polyene antibiotics: Nystatin, Amphotericin

Nitro imidazole: Tinidazole, Metronidazole.

Nicotinic acid derivative: Isoniazid, Pyrazinamide, Ethionamide.

Others: Rifampicin, Ethambutol

Azole derivative: Ketoconazole, Tiniazole, Miconazole.

Based on Spectrum of activity

Narrow spectrum: Penicillin, Streptomycin, Erythromycin

Broad spectrum: Chloramphenicol, Tetracycline.

2. Based on Mechanism of Action

Inhibit cell wall synthesis: Penicillin, Cephalosporin, Cycloserine, Vancomycin,

Causes leakage from cell membrane: Polyene antibiotics such as Amphotericin,

Nystatin, Bacitracin.

3. Inhibit protein synthesis: Tetracycline, Erythromycin, Clarithromycin.

Causes misreading of m RNA code: Aminoglycoside

Inhibit DNA gyrase: Nalidixic acid, Sparfloxacin, Norfloxacin

Interfere with DNA function: Metronidazole, Rifampicin.

Interfere with DNA synthesis: Zidovudine, Acyclovir.

Interfere with metabolism: Sulphonamide, Para-amino alicyclic acid.


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4. Antibiotics obtained from

Fungi: Penicillin, cephalosporin, Griseofulvin.

Bacteria: Bacitracin, Polymixin.

Actinomycetes: Tetracycline, Chloramphenicol, Aminoglycoside.

5. Types of action

Primarily Bactericide

Primarily Bacteriostatic

Quinolone antibacterial

The first clinically useful quinolone antibiotic was discovered from chloroquine, antimalarial

drug, it was discovered by scientist Lesher and its co-workers in 1962. The Nalidixic acid

was the first discovered fluroquinolone.[3]

Quinolone are new class of synthetic antibiotic, so

it is effective against urinary tract infection and gastrointestinal tract infection, respiratory

tract infection, skin infection, Sexually transmitted diseases. It showed bactericidal and broad

spectrum of activity. It was effective against gram negative bacteria due to its ability to bind

with high amount of proteins.

Classification of Quinolone

Depending upon Generation

1. First Generation: Nalidixic acid was first synthetic fluroquinolone antibiotics. These are

the drug effective against gram positive and gram negative bacteria.at lower concentration

the nalidixic acid is inhibiting the growth of microorganism and at higher concentration;

the nalidixic acid is killing the bacteria instead of inhibiting growth of microorganism.

[24]The nalidixic acid drug, which has ability to inhibiting the DNA replication by binding

with DNA gyrase enzyme.[24]

E. g. Nalidixic acid, Oxolinic acid.

Fig. no. 1: Structure of Nalidixic acid.


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Chemical Name: 7-methyl- 1-ethyl-4-oxo-3-carboxylic acid -1, 8-Naphthyridine

2. Second Generation: These are effective against gram negative bacteria. It has more half-

life as compared to first generation.

e. g. Ofloxacin, Lomefloxacin, Norfloxacin, Enoxacin, Ciprofloxacin.

3. Third Generation: these are effective gram positive and gram negative bacteria.

e.g. Temafloxacin, Sparfloxacin, Grepafloxacin.

4. Fourth Generation: It is active against anaerobes, atypical bacteria.

e. g. Moxifloxacin, Gatifloxacin.

Fig. no. 2: Structure of ciprofloxacin and Norfloxacin.

Chemical Name of Norfloxacin: 1- ethyl 6-Flouro,7-piperazinyl 4-oxo, 3-carboxylic acid

quin-1-olone.

Chemical Name of Ciprofloxacin: 1- cyclopropyl, 6-Flouro,7-piperazinyl 4-oxo-3-

carboxyxlic acid quin-1-olone.


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Mechanism of action of quinolone

Fig. no. 3: Schematic representation of mechanism of action of fluoroquinolones.

Fluroquinolone are the drugs which, inhibit the DNA gyrase enzyme, DNA gyrase enzyme

which nicks the double stranded DNA and induces negative supercoiling of DNA. DNA

gyrase enzyme consist of two types of genes such as gyr A, gyr B so in this case , gene A has

ability to nicks the double stranded DNA and gene B, induces negative supercoiling of DNA.

thus Fluroquinolone binds with gyrase A subunit with high affinity, so, it is interfere with

cutting of DNA strands and interfere with resealing of DNA strand but it is observed that the

gram positive bacteria, is major target of drugs. Then, The topoisomerase II is a enzyme

which induces negative supercoiling of DNA strands.[4,6]


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Structural activity relationship

Fig no 4 SAR of Quinolone antibacterial.

1. Position 1: If substitution of bicyclic ring system it exert its key effect on therapeutic

effect of this drugs and usually it also improves the pharmacokinetic effect and enhance

the antibacterial activity e. g. Moxifloxacin, however these modification may produces

adverse effect on human being. If substitution of cyclopropyl group at N 1 position this

modification usually shows increase in antibacterial activity against typical bacteria such

as Chlamydia, mycoplasma. If substitution of 2, 4 diphenyl group at N1 position it

improves the antimicrobial activity e. g. Temafloxacin, Trovafloxacin but nowadays,

Trovafloxacin has been withdrawn from market due to its liver toxicity.

a. 1, 8 Naphthyridine nucleus is responsible for antibacterial activity. If attachment of side

chain at N1 position by any groups it significantly affect antibacterial activity. If

substitution of methyl or amino group at N1 position it improved the antibacterial activity

e. g. Sparfloxacin- Substitution of methyl group at N1 position.

b. The side chain attached with nitrogen containing atom, it significantly affects the potency

of drug.[31]

2. Position 2: If reduction of double bond at position 2, 3 it eliminates antibacterial activity.

If substitution of any group at 2 positions it interfere with DNA gyrase enzyme- substrate

complex or it may inactivate the molecule.


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3. Position 3: The attachment of carboxylic acid at 3 position is very close to the binding

site of DNA and this Pharmacophore is binds to the bacterial DNA gyrase of cell but it

does not interfere with stereochemistry of compound.[31]

a. If replacement of carboxylic acid by the Isothiazole, which is heterocyclic compound thus

it produces Isothiazquinolone compound which have 4- 10 times antibacterial activity as

compared to the ciprofloxacin but it appears that this new compound has mammalian

toxicity.

4. Position 4: the keto group at 4 position which is important moiety and essential for

antibacterial activity.

5. Position 5: If substitution of another group at C 5 position, it improves an antibacterial

activity against gram positive bacteria. If substitution of bulky substituent at C-5 position

it markedly reduces the antibacterial activity means substitution of methyl group at 5

positions, it decreases the antibacterial activity.

e.g. Grepafloxacin, sparfloxacin.

6. Position 6: If substitution at 6 position by F atom it increases the lipophilicity of drug

molecule means it increases the penetration power of compounds through the cell wall of

bacteria. It also helps in binding with DNA gyrase and topoisomerase enzyme.Carboxy 4-

pyrido is essential for antibacterial activity.

7. Position 7: If substitution at 7 positions by heterocyclic compounds by piperazinyl group

and pyrrolidinyl group, it represents the most significant antibacterial activity. E. g.

Ciprofloxacin, moxifloxacin.[31]

If substitution at 7 position by another group, it is

increases the binding of drugs to the CNS hence, it shows CNS side effect. If substitution

of alkyl group on piperazine ring for example ofloxacin it decreases binding ability to

GABA receptor.

8. Position 8: If substitution of F atom at 8 position of quinolone nucleus , it increases the

half-life and drug absorption of drugs but it induces the photosensitivity reaction So it is

important to overcome and eliminate the photosensitivity reaction so, the methoxy group

has been substituted at 8 positions.[32]

9. If introduction of third ring to the nucleus of quinolone e. g. ofloxacin has asymmetric

carbon atom at 3 position hence it was observed that ofloxacin has two types of isomers


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such S (-) levofloxacin and R (+) isomer hence, the levofloxacin is 8-128 times more

potent as compared to the R isomer. Though, Levofloxacin has more binding ability to the

DNA gyrase enzyme.

10. The polyvalent metal ion having ability to bind with quinolones so this chelation

decreases the drug absorption and solubility of drug molecule.

Pharmacokinetics

Fluroquinolone are well absorbed through oral route with good bioavailability It has more

half-life due to its high binding ability. It is reached high plasma concentration within few hrs

and It has been excreted in urine.

Therapeutic applications

It is used in treatment of Prostatitis, Urinary tract infection, ciprofloxacin drug has been used

as a first choice of drug in treatment of typhoid fever, but ampicillin, clotrimazole drugs has

produces resistance to it, hence it is not used in treatment of typhoid fever. These are used in

the treatment of Chancroids, Gonorrhea. Used in bone and tissue infection. If any drug

produces resistance to the bacteria so, quinolone antibacterial has been used in treatment of

tuberculosis. Similarly, Levofloxacin is used in treatment of respiratory tract infection caused

by Legionella, Chlamydia, Mycoplasma.

Side effect

The quinolone shows tendon rupture and if sparfloxacin and grepafloxacin have been used it

produces prolongation of QT interval, the agranulocytosis and Anaphylaxis have been

already reported, due to use of quinolone antibacterial. Skin photosensitivity has been

reported during the use of fluroquinolones. (Review on flouroquinolone)

Toxicities

Gratifloxacin is causes cardiac toxicity. Trovafloxacin produces liver toxicities hence;

trovafloxacin has been withdrawn from market.

Contraindications

The quinolones drugs should be avoided in patient whom are suffering from the epilepsy,

Marfans Syndrome, QT interval prolongation or patient who have had stroke problem.

Quinolone should be contraindicated in children’s due to risk of musculoskeletal


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disorder.Moreever, it should be avoided in patients who have hypersensitivity reaction and

allergy to the quinolone antibiotics.[16,21]

Beta lactam antibiotics

Penicillin

The antibiotics have main structural unit are beta lactam ring system. Lactam ring consist of

cyclic amide group and ester group. The structure of lactam ring consists of carbon atom at 2

positions which was designed as beta, at 3 positions was designed as beta. The cotemptory

name of Beta lactam ring is Azetididione.

History of Penicillin

A penicillin antibiotic was first discovered by Alexander Flaming in 1941.[15]

This was

originally discovered from Penicillinium notatum. Alexander flaming has postulated that,

there is existence of certain kinds of bacteria. he was working on the disease causing bacteria

he observed or postulated that the formation of green coloured mold Penicillium

chrysogenum which may contain the antibacterial agent and he has named the antibacterial

agent as ‘Penicillin’. Fleming has exploits the penicillin as antibacterial agent.[28,2,4]

Nomenclature of Penicillin

Fig. no. 5: Nomenclature of Penicillin.


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The nomenclature of penicillin are divided into two types

1. Chemical Abstract System

2. United State Pharmacopoeia

1. Chemical Abstract System[4]

The chemical abstract system, The structure of penicillin contains sulphur atom which is

assigned as 4 number hence the name of compound are 6-acylamino-2,2-dimethyl-3-

carboxyxlic acid.

2. United State Pharmacopoeia

The United State Pharmacopoeia, this system is reverse of chemical abstract system. The

nitrogen atom is assigned as 1 number and sulphur atom is assigned as 4 numbers so the

names of compound are 4-thia 1 –azabicyclo heptane.[4]

Chemistry of Penicillin

In chemistry of penicillin If beta lactam ring is fused with thiazolidine ring system.it is

known as Penicillin, this fusion shown as V shape cyclic structure. If beta lactam is fused

with tetra hydro thiazolididione and if beta lactam ring fused with.

In penicillin antibiotics, If removal of side chain from penicillin, by amidase enzyme it

produces the 6-Amino penicillanic acid or if attachment of another side chain on nucleus of

penicillin it may affect the pharmacokinetic properties of drugs. If attachment of Na+ and K+

ion at the end of carboxyl group, salt formation occurs, so this salt formation are more stable

as compared to the parent drug. Penicillin G are more stable in dry state and it is stable at 4-50

C temperature therefore, penicillin drugs should be prepared freshly before use of drug.[2]

Classification of Penicillin[32]

1. Fermentation Derived penicillin e. g. 6-aminopenicillanic acid, Benzyl-penicillin,

Phenoxy-methyl penicillin.

2. Semi synthetic Penicillinase resistant Parenteral penicillin e. g. Methicillin, Nafcillin.

3. Semisynthetic Penicillinase –Resistant oral penicillin e. g. Oxacillin, Dicloxacillin.

4. Semisynthetic Penicillinase –Sensitive, Broad spectrum Parenteral penicillin e. g.

Carbenicillin, Mezlocillin, Piperacilin.

5. Semisynthetic Penicillinase –sensitive Broad spectrum oral penicillin. e. g. Amoxicillin,

Ampicillin.


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Chemical instability of Penicillin

Penicillin is undergoes degradation by using Beta lactamase enzyme so, it produces the

formation of Penicilloic acid and Penilloic acid.

Fig. no. 6: Chemical Instability of Penicillin.

Mechanism of action of Penicillin

In case of gram positive bacterial, bacterial the cell wall is made up 50-100 molecules which

is thick in nature. But in case of gram negative bacteria, the bacterial cell wall is made up of

2-3 layers which is thin in nature. The cell wall is made up of Peptidoglycan layer.

Peptidoglycan is hetero-polymer which provides rigidity to the structure of cell wall and it is

cross linked with each other. Peptidoglycan layer are made up of two components such as

sugar and peptide chain, therefore UDP-N-acetyl glutamic acid and UDP-N-Acetyl muramic

acid as a sugar moiety and D-ala-D-ala it is further undergo racemization with L-ala. This

peptide chain cross-linked with each other by using Trans peptidase enzyme. These Trans

peptidase enzyme are also known as Penicillin Protein binding. Penicillin binds to trans

peptidase enzyme, therefore it inhibits the cell wall synthesis by inhibiting trans peptidase

enzyme means it inhibits penicillin binding protein. The penicillin binding proteins are

responsible for cell division so, if inhibition of trans peptidase causes cell lysis.


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Fig. no. 7: Structure of Peptidoglycan.

Fig. no. 8: Mechanism of action of Antibacterial agents.

SAR of Penicillin

Fig. no. 9: SAR of Penicillin.


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1. Beta lactam ring is essential for activity.

2. The free Carboxyl group is important for activity.

3. Bicyclic system is essential for activity.

4. Acyl-amino group is essential for activity

5. Sulphur is not responsible for any activity but it is present at their place.

6. In case Penicillin G or benzyl penicillin are sensitive to acid, there are various reasons for

sensitivity of Penicillin G for acid.

7. The Cis stereochemistry is essential for activity.

1. Ring strain: the ring strain is type of pressure that created in bicyclic ring system due to,

the presence four carbon atom from which, three carbon atom having 900 angle and one

carbon atom having 1800

angle so, it shows ring strain . if greater is the ring strain, greater

is the antibacterial activity but it affect the stability of bicyclic system. The beta lactam

ring consists of four membered lactone ring. The penicillin have large angle or torsional

angle, If acid catalyzation occur at the beta lactam ring of penicillin so, it relieves the ring

strain.

2. A highly reactive beta lactam ring: The tertiary amide group is very susceptible to

nucleophilic attack, but beta lactam carbonyl group is not susceptible to nucleophilic

attack, this is due to stabilization of carbonyl group of tertiary amide. The carbonyl group

does not have similar reactivity with tertiary amide group.

3. The beta lactam ring consists of carbonyl oxygen and nitrogen atom. In case of beta

lactam ring the nitrogen atom is unable to withdraw the lone pair of electron from

carbonyl oxygen so it would be converted to the flat shape structure of bicyclic system.

As a result, a lone pair of electron from carbonyl oxygen feed to the nitrogen atom

therefore, the nitrogen atom become nucleophilic in nature and carbonyl group become

electrophilic in nature. In tertiary amide group is less susceptible to the acid attack so, due

to resonance effect the electrophilic character of carboxyl group is reduced by them.

4. It has been observed that beta lactam ring is a vital group for antibacterial activity so if it

is replaced by another group, no antibacterial activity has been observed. The acyl amino

group is a neighboring group which affects the pharmacokinetic property of drug. If

substitution of electron withdrawing group at the side chain of acyl amino group. Due to


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inductive effect, the electrons are pulling away from carbonyl oxygen. It also reduces the

nucleophilic character of the carbonyl oxygen.

5. Penicillin V has electron withdrawing group on side chain of acyl amino group so, it has

more acid stability as compared to the Penicillin G because, the penicillin V is survive to

enough in gastric mucosa of stomach hence, penicillin V always administered by the oral

route of administration. However the penicillin V is more sensitive to the Penicillinase

enzyme as compared to the Penicillin G.[3]

Side Effect

The penicillin is the safest drug among all the antibacterial agents so the According to Food

Dug Administration, the drugs are classified pregnancy class A and pregnancy class B. the

pregnancy class B is the safest drug and it produces skin rashes and hypersensitivity reaction.

In case of ampicillin, it produces gastrointestinal disturbances.[9]

Individual penicillin

Benzyl penicillin: Penicillin G is effective against the gram negative cocci, Due to its

cheapness and low toxicity.[32]

Beta lactamase inhibitor

Sulbactam

Sulbactam is beta lactamase inhibitor The beta lactam antibiotics given in combination with

sulbactam so, it is inhibiting the beta lactamase enzyme present in bacteria and destroys the

activity of beta lactam antibiotics[23]

also, it is a derivative of beta lactam antibiotics.

Sulbctam is prepared from penicillin. the structure of penicillin consist of sulphur atom so,

this sulphur atom undergoes the oxidation to forms sulfone therefore, Sulbactam and

amoxicillin are the more effective combination in treatment of infection and not all beta

lactamase drugs are sensitive to sulbactam and clavulanic acid.[30]

Sulbactam and Ampicillin are the effective combination for treatment of skin infection

caused due to the bacterial strain such as Escherichia coli, Staphylococcus aureus.[23]


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Fig. no. 10: Structure of Sulbactam.

Chemical name: Sodium (2, 3) 3, 3-dimethyl 7-oxo-4-thia-1-azabicyclo [3.2.0] heptane 2-

carboxylic acid 4,4 –dioxide.

Novel β lactam Antibiotics

The Penicillin and Cephalosporin are the effective β-lactam antibiotics.

Clavulanic acid: The Clavulanic acid was first isolated from Streptomyces clavuligerus in

year of 1976. It has weak antibacterial activity. Clavulanic acid is β lactamase inhibitor. It is

used in combination with amoxicillin antibiotics, this combination used to improve the

spectrum of activity and it also reduces the amoxicillin concentration. The clavulanic acid

been fused with oxazolidine ring system instead of it was not fused with thiazolidine ring

system or sulphur containing ring system. The various analogues have been prepared to

increase the β lactamase activity. The clavulanic acid consists of β lactam, double bond with

Z configuration. There is no substitution at 6 positions; It does not have acyl amino side

chain, carboxylic acid. Clavulanic acid is suicide substrate, the clavulanic acid is fits the

active site of the β lactamase so, β lactam ring is opened by the serine residue, same as

penicillin.

Olivanic acid: The Olivanic acid was isolated from strains of Streptomyces olivaceus. They

are 1000 times more potent than clavulanic acid. They have strongest β- lactamase activity.


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Fig. no. 11: Structure of olevanic acid.

Cephalosporin

Cephalosporin is β lactam antibiotics it has good pharmacokinetic property with low toxicity.

It has broad spectrum of activity. According to spectrum of activity, cephalosporin is

classified into four classes. Cephalosporin is more effective than penicillin G. Moreover,

when patients are allergic to the penicillin, cephalosporin has been used as a replacement

drug.

Nomenclature

The structure of cephalosporin antibiotics consist of bicyclic system along with

dihydrothiazine ring system. The saturated ring system is known as cepham (5-thia,1-

azabicyclo(2,3) octene] ring. The cephalosporin is commonly known as cephamycin C.

Fig. no. 12: Nomenclature of Cephalosporin.


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In this case the numbering starts from the nitrogen atom so, in this case the chemical name of

Cephalothin is 3-(acetoxymethyl)-7-[2-(thienylacetyl)amino]-8-oxo-5-thia-1-azabicyclo oct-

2-ene.

Classification

First generation

The first generation of cephalosporin are effective against the aerobic gram positive cocci and

the cephalothin drug has very short half-life of drug and cephaloridine causes the

nephrotoxicity and it is effective against gram negative bacteria and has broad spectrum of

activity.[16,29]

(Antibiotics).The most of first generation drugs such as cephazolin drugs

effective against the methicillin sensitive staphylococcus aureus and gram negative bacilli.

This are prescribed in treatment of surgical site infection (SSI) as a combination and

monotherapy. These are effective in treatment of diabetic foot infection and pharyngitis as a

monotherapy.[14]

e. g. Cephalexin, cefazolin, cephalothin, cephadroxil, cephradine.

The first generation cephalosporin drug has poor absorption power, when it has taken by oral

route of administration.

Fig. no. 13: Structure of cephalothin.

Chemical Name: (3-acetoxymethyl)-7-[2-(thienylacetyl) amino]-8-oxo-5-thia-1-azabicyclo

oct-2-ene.

At the 3-position the substitution of acetoxy group which is susceptible to hydrolysis hence, it

may convert the active group to inactive metabolite by using esterase as an enzyme.


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Second generation

Second generation drugs ineffective against the gram negative bacilli and it is more stable

against the Beta lactamase enzyme. The second generation drugs have been used in

veterinary medicines.[16,29]

Cefoxitin is a drug which is effective against the aerobic and anaerobic bacteria. e. g it is

active against the pelvic diseases and pelvic abscess. Cefoxitin is the only one drug which has

been administered by oral as well as parenteral route of administration.

Fig. no. 14: Structure of Cefachlor.

IUPAC name: 2-amino (2-Phenyl acetyl amido)-7-oxo-5-thia-1-azabicyclo( oct-2-ene)-2-

carboxyxlic acid .

A Cefachlor drug has been used as a second generation cephalosporin also in treatment of

otitis media. It is used as an alternative drug to the amoxicillin. If cefachlor used in younger

children, then there is chances of serum sickness syndrome. The various symptoms occur

during the serum sickness syndrome such as allergy or skin reaction, lymphadenopathy and it

may last for 6-12 days. It can be cure by stop the use of cefachlor.[25]

Uses: It is used in treatment of septicemia, pneumonia, meningitis, biliary tract infection,

urinary tract infection.

e. g. Cephachlor, Cephadoxil, Cefoxitin

Third generation

Cefotaxime is a drug which inhibits the Beta-lactamase enzyme but it is effective against the

many bacteria. The cefotaxime should be given to patient after 4-8hrs if any patient suffering


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from serious infection. This drug undergoes metabolism to form desacetylcefotaxime but it is

less active against the parent compound. The cefotaxime has been used in N. Meningitis, S.

Pneumonia, H. influenzea.

Cefepodoxime proxetil is similar to the cefepime antibiotic but it is active against and

Enterobacter spp. And Streptomyces spp.[2]

The third generation cephalosporin antibiotic can be absorbed by oral route and it get

hydrolyzed by the esterase enzyme, so the vinyl group is substituted at 3-position of

cephalosporin to avoid the esterification for example in case of Cefixime.[16]

Fig. no. 15: Structure of Cefixime.

Chemical Name

Fourth generation

The fourth generation cephalosporin is effective against the gram positive cocci, gram

negative bacilli including Pseudomonas aeruginosa, some of the beta lactamse producing

Enterobacter species.[26]

Fifth generation

The fifth generation drug is effective against the methicillin resistant staphylococcus aureus,

Penicillin resistant streptococci. These are also effective against gram positive cocci and

gram negative bacilli. But these are not active against Pseudomonas species.[26]

e.g. Ceftaroline, ceftobiprole


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Mechanism of action

Cell wall which provides rigidity to the bacteria. Cephalosporin is beta lactam antibiotics. it

inhibit the cell wall synthesis, The cell wall is made up peptidoglycan ,the peptidoglycan

consist of sugars and peptide chain. The UDP N-acetyl glucosamine and UDP-N-acetyl

muramic acid are type of sugars and L- alanine and D-alanine are the peptide chain. The

penicillin binds to the Trans peptidase enzyme .The trans peptidase enzyme is responsible for

cross linking of peptide chain. So, if inhibition of trans peptidase enzyme, inhibit the cross

linking of chains and cell lysis of bacteria. Hence, cephalosporin has bactericidal activity.

Indications

Sometimes the Ceftriaxone is contraindicated in small children’s or ceftriaxone drug must be

not be coadministerd with calcium containing drugs or solutions because the calcium may

forms the complex with ceftriaxone drug due to precipitation reaction in between both of

them.[26]

Probenecid drug has ability to increase the antibiotic activity of cephalosporin. The

probenecid may increase the renal secretion and half-life of the drug. And when probenecid

administered for three to four times by oral route so, it may increases the antibiotic activity of

cephalosporin.[25]

Side effect

Cephalosporin has been shows various side effects such as Stevens - Johnson syndrome,

gastrointestinal agents such as vomiting, nausea, diarrhea, blood disorders such as aplastic

anemia, leucocytopenia, thrombocytopenia, hemolytic anemia. Cephalosporin has side effect

such as hypersensitivity reaction, sometimes penicillin-sensitive patient will have allergy to

the cephalosporin.[26]

Glycopeptide antibiotics

Vancomycin

The glycopeptide antibiotic was synthesized in 1960. The Vancomycin was synthesized from

Streptomyces orientalis.[13]

The vancomycin antibiotics are effective against gram positive

bacteria. The structure of vancomycin consist of seven amino acids, amino sugars, sugars.

The vancomycin inhibits the cell wall synthesis by forming complex with cell wall

(peptidoglycan) by inhibiting the transpeptidase enzyme.[10]

These are effective against the

methicillin resistant staphylococcus aureus and methicillin sensitive staphylococcus aureus, it


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is effective against gram positive bacteria. However, linezolid and minocycline are effective

against gram positive CNS infection.

Fig. no. 16: Structure of vancomycin.

IUPAC Name

(1S, 2R, 18R, 19R, 22S, 25R, 28R, 40S)-48-[(2S, 3R, 4S, 5S, 6R)-3-[(2S, 4S, 5S, 6S)-4-

amino-5-hydroxy-4,6-dimethyloxan-2-yl]oxy-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-

l]oxy-22-(2-amino-2-oxoethyl)-5,15-dichloro-2,18,32,35,37-pentahydroxy-19-[[(2R)-4-

methyl-2-(methylamino)pentanoyl]amino]-20,23,26,42,44-pentaoxo-7,13-dioxa-

21,24,27,41,43pentazaoctacyclo[26.14.2.23,6

.214,17

.18,12

.129,33

.010,25

.034,39

]pentaconta-

3,5,8(48),9,11,14,16,29(45),30,32,34(39),35,37,46,49-pentadecaene-40-carboxylic acid


861


Pharmacokinetics

The vancomycin antibiotics are administered through the oral and parentral route of

administration so, 90% of drug has excreted though urine in unchanged form and excreted

through glomerular filtration route.[8]

Side effect

The intravenous administration of vancomycin may produces the Red man Syndrome, red

man syndrome/ red neck is type of nonimmunological response which causes the hypotension

and pruritis, Similarly, The vancomycin may causes the ototoxicity ( loss of hearing due to

damage of 8th

cranial nerve), hypersensitivity reaction.[8]

Tetracycline

Tetracycline being a family of antibiotics although it was discovered from Streptomyces

aureofaciens. Tetracycline structure consist of ring A, B, C,D. Tetracycline are a broad

spectrum antibiotics which was discovered as natural products so, it is effective against gram

negative and gram negative bacteria. The chlortetracycline and Minocycline are the basic ring

system of tetracycline.[30]

Mechanism of Action

Tetracycline drugs inhibit the protein synthesis by binding to the 30 S ribosomal units. First

we have discussed about the protein synthesis in animal and human being. The mRNA

consist of codons and anticodons, ribosome consist of three types of subunits 70S, 50S, 30S,

so the tRNA has major role in protein synthesis. The tRNA brings the amino acid chain on

the A site attachment site, and after some time it shifts from attachment site to P site due to

conformational changes in mRNA, finally it shifts to S site, means protein synthesis

site.meanwhile,it increases the addition of amino acid on P,S site. However, the tetracycline

is binds to the 30 S bacterial ribosomal subunit and it preventing the access of tRNA to the

acceptor site hence, it prevent the formation of complex of ribosome-30S, so it inhibit the

protein synthesis.[2]

SAR of Tetracycline[17]

1. Tetracycline and its analogue consist of Napthacene carboxamide basic nucleus. They

have numbers A, B,C and D so, the numbering starts from D ring and at second position,

the structure possess –CoNH2 group which imparts antibacterial activity.


862


2. If replacement of –CONH2 at 2 positions by another atom, it has more antibacterial

activity due to bacteria poorly accumulate on this moiety. When replacement of nitrogen

atom by another atom, it may significantly imparts water solubility.

3. If we do the addition and deletion of ring A, B, C, D ring from the structure, it decreases

the antibacterial activity.

4. The presence of dimethyl amino group at 4 positions, which is existence as antibiotic

activity/ properties, it possesses the antibacterial activity against the gram negative

bacteria but if it is undergoes the epimerization so, it decreases the antibacterial activity.

5. The keto-enol tautomer’s in between C1 and C3 atom of the Ring A which has been

essential in inhibition of protein synthesis.

6. If attachment of sulphur atom at 6 position of tetracycline (Thiotetracycline) is apparent

exception case, because the first requirement for increase in antibacterial activity is that,

the six membered ring is essential for antibacterial activity. Some of the tetracycline has

found in the forms of prodrug so, it is enters the in vivo system, it liberate free

tetracycline.[16,17,18]

Fig. no. 17: SAR of Tetracycline.

If substitution at 9-position by nitro group, it leads to poor antibacterial activity

Chemical properties

1. The tetracycline molecule has offered a splendid challenge to a synthetic organic chemist,

a major obstacle in its total synthesis being the stereospecific introduction of many

functional groups into the basic carbon nucleus. Of even greater concern is the extreme

chemical sensitivity of this molecule, particularly its lability in acidic media.


863


The first synthesis of a tetracycline-like molecule with the functionality necessary for

antimicrobial properties was accomplished by the legendary Robert B. Woodward and a

group at Pfizer (Some earlier work utilized completely aromatic precursors in conventional

acylation reaction to form the C(11), C(12) b-diketone system. The product, sancycline (6-

demethyl-6-deoxytetracycline), is an active antibiotic, but not used as often as aureomycin or

tobramycin. The Woodward's synthesis is completely linear and involves incorporation of the

4-dimethylamino- group and the 12a-hydroxy- group into the final structure. The synthesis

provides a dramatic illustration of the importance and creativity of organic chemistry.[27]

Fig. no. 18: Synthesis of tetracycline.


864


Fig. no. 19: Structure of Chlortetracycline.

Pharmacokinetic

When Tetracycline is administered by oral route it has incomplete absorption of drug so,

there is rise in concentration of percent unabsorbed drug. Although, it should be avoided with

concurrent ingestion of milk products due to milk contains calcium ion so, the tetracycline

forms a complex with calcium ion e.g. tetracycline –calcium complex. Doctor recommended

that to avoid the concurrent administration of milk products with tetracycline. It has peak

plasma concentration of 2-4hrs. It should be administered after 4-6 hrs, it has very short half-

life. The doxycycline and minocycline are produces complete absorption of drug through oral

route so, it is not necessary to take a frequent administration of these drugs.

Resistance

The tetracycline may produces the resistance two reasons are as follows: i) to production of

protein, that displaces the tetracycline from its target site this may occur due to change in

sequence of base pairs in DNA strands.ii)Accumulation of tetracycline.

Uses

It has been used in riketssial infection such as tetracycline and Doxytetracycline are first

choice of drug in treatment of Rocky mountain spoty fever, Pneumonia.

It has been used in Sexually transmitted disease, it is used in treatment of urinary tract

infection against the E.coli, it is used by oral and topical route, in treatment of acne,

traveller’s diarrhea.


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Side effect

It causes the Discoloration of teeth, Bone marrow depression, Nephrotoxicity.

Mechanism of antibiotic resistance

Antibiotic are the drug which synthesized from microorganism or which kill or inhibit the

growth of microorganism. An organism may develop to many antibiotics, the resistance may

transfer from individual bacteria to another. Resistance gene may transfer from one bacteria

to another bacteria through mobile genetic element. It is clinically important and effective

against multidrug resistant of gram negative bacteria but when resistance has compared

thorough mutation, the multidrug resistance has more effective method.

There are various methods for antimicrobial resistance mechanism such as: Horizontal gene

transfer, Inactivation of antibiotics, intrinsic resistance.[15]

AKNOWLEDGEMENT

The author would like to express their gratitude to the Principal of Annasaheb Dange College

of B. Pharmacy, Ashta for their provocation and support.

CONCLUSION

The comprehensive studies of antimicrobial agents and antibacterial antibiotics have been

done. It includes beta lactam antibiotics (Penicillin, cephalosporin) tetracycline, glycopeptide

antibiotics, Quinolone antibacterial. It has been observed that nowadays, the antibiotics and

antimicrobial agents have the imperative role in daily routine due to change in life style and

due to increase in growth of microorganism and its infection.

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