Antibiotics

Antibiotics: means against life Definition: Antibiotics are compounds that are derived from certain micro-organisms and that inhibit the growth of other micro-organisms.  Selectively toxic for bacteria • Bactericidal • Bacteriostatic  No harm to patient  Destroy structures present in bacteria, not in host.

Classification of Antibiotics  Based on Chemical structure • Sulphonamides- Dapsone, PAS • Diaminopyrimidine derivatives- trimehoprim • Quinolone derivative – Norfloxacin,Ciprofloxacin • Beta- Lactam ring – Penicillin, Cephalosporin • Tetracyclin- Chlortetracyclin, Oxytetracyclin, Doxytetracyclin • Nitrobenzene derivatives- Chloramphenicol • Aminoglycoside- Streptomycin, Gentamycin • Macrolide- Erythromycin, Azithromycin • Polypeptide derivatives- Polymyxin-B,Bacitracin • Glycopeptide derivatives- Vancomycin • Nitrofuran derivative- Furozolidine • Nitroimidazole derivatives- Metronidazole, Tinidazole • Nicotinic acid derivatives- Isoniazide, Pyrazinamide • Polyene derivatives- Amphotericin-B • Azole derivatives- Ketoconazole, Fluconazole  Based on mode of action • Inhibit cell wall synthesisPenicillin,Cephalosporin,Cycloserine, Bacitracin • Cause leakage from Cell membranePolymyxin,Amphotericin-B

• Inhibit Protein synthesisTetracyclin,Erythromycin,Chloramphenicol • Cause misreading m-RNA and affect permeabilityAminoglycoside • Inhibit DNA gyrase-Ciprofloxacin, Norfloxacin • Interfere with DNA synthesis- Acyclovir, Zidovudine • Interfere with DNA function- Rifampin,Metronidazole • Interfere with intermediary metabolism- Sulphonamide, Pyrimethamine, Ethambutol Beta Lactam Antibiotics: Structure of Beta-Lactam ring:

Penicillin: Penicillin is obtained from various species and strains of penicillium. e.g. • Penicillium notatum , • Penicillium crysogenum Classification of Penicillin  Natural Penicillin

• Extracted from the cultural solution of penicillium • Proto type is penicillin G • PH Sensitive (Not given orally) • Effective against Gram positive bacteria • Susceptible to enzyme penicillinase  Semi synthetic Penicillin • Produced by growing penicillium in culture ( synthesis of main nucleus) • Structural modification done in Lab. • Broad spectrum antibiotics, effective against Gram negative bacteria also • Are not resistant to enzyme penicillinase. E.g.- Penicillin-V, Oxacillin, Ampicillin, Amoxycillin  Mode Of Action o Prevent the formation of bacterial cell wall by interfering with the synthesis of Peptidiglycan.  Chemistry of Penicillin • Chemically they are carboxamido derivatives of Penicillonic acid.

• Main nucleus of penicillin : 6-Aminopenicillanic acid

• It is a fused form of Beta-Lactam and thiazolidine ring. • Hydrolysis product of Penicillin with reference to enzyme

 Amidase: 6- Aminopenicillanic acid  Penicillinase: Penicillonic acid

SAR of Penicillin

• Bicyclic ring system or Beta Lactam ring is essential for antibacterial activity

• Amide group attached to Lactam ring is essential for antibacterial activity. Acyl group present in amide is bind at protein and inhibit cell wall synthesis • Cis stereochemistry of hydrogen is essential for antibacterial activity • Free carboxylate is essential for stability • Different acids in the fermentation medium give different penicillin. Biosynthesis:

Therapeutic Use: Penicillin G is the first choice for • Streptococcal infection • Pneumococcal infection • Staphylococcal infection • Meningococcal infection • Gonococcal infection • Syphilis infection

AMINOGLYCOSIDE: • Basically all the Aminoglycosides are isolated from soil actinomycetes, Streptomyces griseous. • All the Amino-glycoside antibiotics chemically contains basic six membered ring (Substituted with amino or Guanidino group) to which one or more amino sugar are attached through a glycosidic linkage. • Six membered rings: Streptidine ring • Amino sugar: Glucosamine or Neosamine, N-methyl-1-Glucosamine

Different member of Aminoglycosides: • • • •

Streptomycin Gentamycin They have broad spectrum activity against Gram negative bacteria. Neomycin Kenamycin

Mode of action:

Aminoglycoside combine with bacterial ribosome and block the protein synthesis. Streptomycin: • Streptomycin is isolated from Streptomyces griseous, grown in nutrient media or fermentation media. (Soil Actinomycetes) • Antimicrobial spectrum is relatively narrow, primarily active against Gram negative bacilli, but potency is low. • Chemically Streptomycin having polybasic amino groups i.e. Streptidine linked glycosidically to two or more amino sugar i.e. Lstreptose and N-methyl-1- glucosamine. • Chemical structure:

SAR of Streptomycin: o Streptidine ring is essential for bioactivity.

o Axial hydroxyl group at C-2 is essential for bioactivity.

o Two highly basic Guanidino groups at C-1 and C-3 in place of the

primary amine moieties of 2-deoxystreptamine or N-methyl-1glucosamine are essential for bio activity. o N-acetylation, O-phosphorylation, and O-adenylation of specific functional group make it resistant. Biosynthesis: In general they are prepared biosynthetically from an admixture of carbohydrate component i.e. D-glucose, in fermentation media.

Therapeutic Use: • Primarily used in treatment of tuberculosis and UTD (urinary tract disease) • Used in treatment of bubonic plague. • Used in treatment of sub acute bacterial endocarditis.

TETRACYCLIN:  Tetracycline is a group of antibiotics obtained by process of

fermentation of different species of Streptomyces belonging to Actinomycetes.E.g. • Streptomyces aureofaciens • Streptomyces rimosus • Streptomyces xanthophaeus  Tetracycline is prepared by removal of chlorine from chlortetracycline by the process of hydrogenation.  Different member of this group is – • Chlortetracycline • Oxytetracyclin • Doxycyclin • Methacyclin • Minocyclin • Lymecyclin • Demeclocyclin  Mode of action: Inhibit the protein synthesis by binding to 30s sub

unit of ribosome and preventing t-RNA from combining with m-RNA. Characteristic feature of Tetracycline: • Yellow crystalline, odourless powder, stable in air • Usually darkens on exposure to strong sun light • Potency of tetracycline seriously affected in solutions of PH below 2. • Destroy rapidly by alkali solution. • PH range of aqueous suspension of tetracycline (1mg/ml) is 3-7.

• Solubility profile: 1gm soluble in 2500ml of water 1gm soluble in 50ml of ethyl alcohol 1gm is freely soluble in dilute acid or alkali solution 1gm is almost insoluble in ether or chloroform.

Chemistry of Tetracycline: • Tetracycline is characterized by highly functionalized partially reduced Napthacene ring as main nucleus.

• It is having octahydronapthacene skeleton made up of four fused ring.

• Structure of Tetracycline:

Name Tetracycline Oxytetracycline Doxytetracycline

X H H H

R1 OH OH H

R2 CH3 CH3 CH3

R3 H OH OH

SAR of Tetracycline: α- stereo orientation of dimethyl amino moiety at C-4, is essential for bioactivity. • Most of the natural tetracycline has a tertiary and benzyl hydroxyl group at C-6. This function has the ideal geometry for acid catalyzed dehydration involving the C-5a, oriented hydrogen which is responsible to impart colour. • Chlorine at C-7 position responsible for photo toxicity by absorbing light in visible region leading to free radical generation and potentially cause severe erythrma to sensitive patients on exposure to strong sun light. • For the high level of antimicrobial activity of tetracycline, substitution on the C-5 and C-7 is not an essential requirement. •

Biosynthesis: • Proceeds by a complex sequence of transformations involving condensation of Malonamyl Co-A and eight malonate units. • Polyketide formation • Process is quite analogous to fatty acid biosynthesis but differs in majority of the carbonyl groups remains in the molecule and self condense to form partially reduced Napthacene nucleus. • After formation of main nucleus it involves sequential reduction, oxidation, methylation, amination and dehydration reaction to complete the biosynthesis of tetracycline.

Therapeutic Use: Broad spectrum antibiotic. First choice in: • Treatment of venereal disease • Treatment of Atypical pneumonia due to mycoplasma pneumoniae. • Treatment of cholera • Treatment of brucellosis • Treatment of plague

• Treatment of UTD and Amoebiasis Chlortetracycline is used as topically for ophthalmic purpose.