ANTIBIOTICS Classification according chemical structure similarity I. ß-Lactam antibiotcs II . The Aminoglycoside Antibiotics III . The Macrolide Antibiotics IV : Antibiotics with fused ring systems: V. Lincomycins VI. Polyenes Antibiotics (Antifungal Antibiotics) VII .Polypeptide Antibiotics VIII.Unclassified antibiotics
A. Penicillin • Natural penicillin • Penicillin G; benzylpenicillin • ß-Lactam thiazolidine penam penicillin penicillanic acid
Semisynthetic Penicillins: • When creating the semisynthetic Penicillin, the task was posed of producing drugs : • 1-Not sensitive to the action of Penicillinase, (the latter is produced by a number of bacteria) because it decomposes, i.e. inactivates penicillin. • 2-Resistant to acids • 3- having a broader spectrum of action than benzyl penicillin.
Structure – Activity Relationships • : • 1-Substitution of an electron withdrawing group at Alfa position of the acyl carbon stabilize the penicillin to acid-catalyzed hydrolysis e.g.. Penicillin V and ampicillin, the increased stability has been attributed to a decrease in reactivity (nucleophilicty) of the side chain amide carbonyl oxygen toward participation in ß–lactam ring opening to form penicillenic acid.
Penicillin V : Phenoxymethyl penicillin • is an acid-stable penicillin given by mouth. • It is used mainly in the treatment of streptococcal • infections and in rheumatic fever prophylaxis PHENETHICILLIN Penicillin V
2-It was found that increasing the steric hindrance at the a-carbon of the acyl group increased resistance to staphylococcal ß-lactamase, with maximal resistance being observed with quaternary substitution. The bulky group interfere with the enzyme attachment to the penicillin and causes conformational change in the enzyme and loss of activity.
Cloxacillin sodium [3-(0-chlorophenyl)-5-methyl-4- isoxazolyl] penicillin
3- The introduction of an ionized or polar group into the a-position of the side chain benzyl carbon atom of penicillin G confers activity against gram-negative bacilli. Hence, derivatives with an ionized a-amino group, such as ampicillin and amoxicillin, are generally effective against such gram –ve genera This selective penetration is believed to take place through the porin channels of the cell membrane
Ampicillin • 6-[D-a-Aminophenylacetamido] penicillanic acid; 6--amino-benzyl penicillin Amoxicillin, 6-[D-(-)--Amino-p-hydroxy-phenylacetamido] penicillanic acid (Amoxil).
4-The incorporation of an acidic substiuent at the a-benzyl carbon atom of penicillin G also imparts clinical effectiveness against gram-negative bacilli and, furthermore, extends the spectrum of activity to include organisms that are resistant to ampicillin .
Carbenicillin Disodium Disodium a-carboxybenzyl penicillin . Its structure shows that it differ from ampicillin by having an ionizable carboxyl group Ticarcillin Disodium, USP. a-Carboxy-3-thienylpenicillin (Ticar) is an isostere of carbenicillin, wherein the phenyl group is replaced by a thienyl group. This semisynthetic penicillin derivative as with carbenicillin,
Salts of Penicillin • Penicillin G procaine
Mode of action of penicillin • . • Inhibit cell wall synthesis by acylation of transpeptidase enzyme necessary for synthesis of dipeptidogycan which responsible for rigidity and strength of the cell wall
Allergy to Penicillins • Allergic reactions to various penicillin, ranging in severity from a variety of skin and mucous membrane rashes to drug fever and anaphylaxis, constitute the major problem associated with the use of penicillin. • Evidence suggests that penicillin, or their rearrangement products formed in vivo (e.g., penicillenic acids) react with lysine-e-amino group of proteins to form penicilloyl protein, which are major antigenic determinants. Clinical observations indicated a higher incidence of allergic reaction with unpurified amorphous preparations, compared with highly purified crystalline forms and with polymeric impurities in ampicillin dosage
Potency • The initially used penicillin was not pure compound; exhibiting varying activity, therefore it was necessary to evaluate it by microbiological mean and the value become known as oxford unit “the smallest amount of penicillin that will inhibit in vitro the growth of a strain of staph in 50ml culture media under specified condition” now, pure crystalline penicillin is available, the USP defines the unit as “the antibiotic activity of 0.6ug of USP penicillin G sod reference standard” • The weight-unit relationship of the penicillin will vary with the nature of the acyl substituent and with the salt formed with free acid
Methods of quantitative analysis . • 1-Iodimetrical determination of the penicillin after the drugs have been hydrolyzed with an alkali (for all penicillin drugs). Since penicillin itself is not oxidized by iodine, but the products of its alkaline hydrolysis are oxidized; penaldic acid and penicillamine, are oxidized by an iodine solution added to the reaction
2. Gravimetry: Benzylpenicillin in drugs containing its potassium, sodium, and procaine salts is determined by the gravimetric method based on the formation of the N-ethylpiperidine salt of benzyl penicillin (the gravimetric form): • 3. Colorimetry : Ampicillin decompose at pH 5.3 for 30 min at 75°C in the presence of copper sulphate. Under these conditions ampicillin decomposes and rearranges to a-aminobenzyl penillic acid, which is estimated colorimetry.
ß-Lactamase inhibitors • Clavulanate Potassium. • Clavulanic acid is an antibiotic isolatedfrom Streptomycesclavuligeris. Structurally it is 1-oxapenam lacking the 6-acylamino side chain of penicillin, but possessing a 2-hydroxyethylidene moiety at C-2. very weak antibacterial activity
Sulbactam • Penicillanic acid sulfone or 1, 1-dioxopenicillanic acid. • This synthetic penicillin derivative is a potent inhibitor of ß-lactamase. it potentiates the activity of ampicillin and carbenicillin against ß -lactamase producing bacteria.
Combinations of amoxicillin and the potassium salt of clavulanic acid are available (Augmentin) in a variety of fixed-dose, oral dosage forms intended for the treatment of skin, respiratory, ear and urinary tract infections caused by b-lactamase producing bacterial strains resistant to amoxicillin alone. Combinations of ampicillin and sulbactam are marketed under trade name Unasyn for the treatment of skin tissue, and gynecologic infections.
B- Cephalosporins: • Cephalosporins are ß-actam antibiotics isolated from cephalosporium • species or prepared semisynthetically Semisynthetic Derivatives: In the preparation of semisynthetic cephalosporins, the following improvements are sought: (1) increased acid stability; (2) improved pharmacokinetic properties, particularly better oral absorption; (3) broadened antimicrobial spectrum; (4) increased activity against resistant microorganisms. (5) decreased allergenicity; and (6) increased tolerance after parenteral administration
Oral cephalosporins • The oral activity conferred by the phenylglycyl substituent is attributed to increased acid stability of the lactam ring resulting from the presence of a protonated amino group on the 7-acyl amino portion of the molecule. • cephaloglycin, is poorly absorbed orally • Cephem CH2OCOCH3
presumably because of solvolysis of the 3-acetoxy group in the low pH of the stomach. The resulting 3-hydroxyl methyl derivative is known to under go lactonization under acidic conditions Cephalexin (Keflex) For urinary and upper respiratory tract infection
Cephradine, USP (Velosef) Available oral and parentral Cefadroxil, USP (Duricef ) Slowly excreted , longer duration of action Cafaclor USP (Ceclor) More potent against homophiles influenza
Parental Cephalosporins • Hydrolysis of the ester function, catalyzed by hepatic and renal esterases, is responsible for some in vivo inactivation of parenteral cephalosporins containing a 3-acetoxymethyl substituent (e.g.cephalothin and cefotaxime). Cephalothin Sodium (Keflin
a second - generation cephamycins It is a semisynthetic derivative 7a-methoxy-substituted cephalosporin Cefoxitin Sodium, (Mefoxin). Cefamandole Nafate (Mandol formate ester of cefamandol Parenteral cephalosporin lacking a hydrolysable group at the 3-position e.g. cephamandole not subject to hydrolysis by esterase's.
Third-generation cephalosporin Wider spectrum of activity meningitis Cefotaxime Sodium (Claforan)
Fourth generation cephalosporin • Cefepim • Cefpirome • R=
II . Aminoglycoside Antibiotics • Aminologlycosides are so named because their structures consist of amino sugars linked glycosidically. • The streptomycin, neomycin, paromomycins, gentamicins, Tobramycins,Kanamycins, and Amikacins • have many chemical and antimicrobial features in common: • All these antibiotics show broad spectrum antimicrobial activity, and paromomycin also inhibits Enatmoeba histolytica. • None of the aminoglycoside antibiotics is absorbed from the alimentary tract, and neomycin has been used widely in the treatment of intestinal infections and chemosterilization of the bowel prior to surgery of that organ
All have at least one aminohexose and some have a pentose lacking an amino group (e.g.. streptomycin) additionally, • each contains a substituted 1,3 - diaminocyclohexane central ring: • in Kanamycin, neomycin, gentamicin, and tobramycin it is deoxystreptamine, • and in streptomycin it is 1,3 - diguanidocyclohexane streptadine
Mechanism of Action • The amino glycosides act directly on the bacterial ribosome to inhibit the initiation of protein synthesis and to interfere with the fidelity of translation of the genetic message. They bind to the 30 S ribosomal subunit to form a complex that is unable to initiate proper amino acid polymerization
Streptomycin . It was shown eventually to be composed of three glycosidcally linked units: streptidine, streptose and N-methyl-L-glucosamine. Showed marked activity against Gram-positive and gram-negative bacteria as well as particular effectiveness against Mycobacterium tuberculosis. In the presence of dilute aqueous alkali streptomycin undergoes a degradative transformation to give gamma- pyrone, maltol. The maltol is derived from the streptose portion of the molecule; it can be readily estimated calorimetrically
Amikacin (Amikin) • 1-N- Amino - hydroxybutyryl Kanamycin. A semi synthetic amino glycoside by acylation of the 1-amino group of the deoxystreptamine ring of kanamycin A with L – amino-hydroxybutyric acid. Active against gram negative bacteria given im or iv not absorbed by mouth.
III . Macrolide Antibiotics • Macrolides are a group of macrocyclic antibiotics containing : • a large non-planar strain less lactone ring (12-16 atoms) • An amino sugar linked glycosidically to the lactone ring, • A neutral sugar linked to the ring or the basic sugar • and contains a ketone group. • Hydrolysis of the glycosidic bonds takes place in acid solutions ,saponification of the lacton ring; in basic-media. • The macrolides are principally active against Gram positive bacteria and show useful activity against penicillin-resistant strains. Also exhibit effectiveness against gram-negative cocci.
Mode of action • Bacteriostatic ,bind to 50 S ribosomal subunit to prevent the translocation step • of bacterial protein synthesis
Erythromycin (Erythrocin) • Erythromycin on hydrolysis provides • a neutral sugar cladinose • Desosamine (a basic sugar) • and the aglycone, • erythronolide. • Clarithromycin semisynthetic • erythromycin • OH at C6 converted to methyl ether
Most of th Most of th Oleandomycin • Oleandolide is a 14-atom • ring that contains an exocyclic • methylene epoxide on carbon 8 Semisynthetic oleondomycin; triacetyl derivative. (TAO); troleandomycin A combination of oleandomycin with tetracyclines, on the basis that it provides a synergistic effect and provides protection against resistant micro organisms (sigmamycin). e
Spiramycin (Rovamycin): • Spiramycin is a macrolide antibiotic produced by the growth of certain strains of streptomyces ambofaciens which has been used similarly to erythromycin. It has also been used to treat protozoal infections and toxoplasmosis.
Azithromycin • Semi synthetic erythromycin with ring enlargement by introduction of N-CH3 between C9 and C10. • It has the following advantages: • More stable to acid degradation • Longer half life once a day dosage • More potent against gm -ve
IV : Antibiotics with fused ring systems: The group includes the broad-spectrum tetracycline. • The Tetracycline • Comprises a group of antibiotics characterized by their common octahydronaphthacene • skeleton.
Rolitetracycline Rolitetracycline is a tetracycline derivative with general properties similar to those of tetracycline . It is included in some topical eye preparations. It has also been given by injection Synthesis Mannich Ter.butyl alc. HCHO PYRROLIDINE
V. Lincomycins They are known as Sulphur containing Antibiotics, act via 50S ribosomal subunit binding & protein synthesis inhibition.They are used in extra CNS anaerobic infections, Penicillin sensitive patients except in respiratory tract infections. LINCOMYCIN CLINDAMYCIN 7S-Cloro-7S-deoxylincomycin semisynthetic
VI PolypeptideAntibiotics • The most powerful antibiotic agents but limited for renal toxicity. • Used mainly locally in burns. • Inhibit mucopeptide cell wall synthesis and interfere with semipermeability of cell membrane BACITRACIN GRAMICIDIN POLYMYXIN (B)
VII.Polyene antibiotics • Macro cyclic lacton 38 atoms • Conjugated polyenes • amphoteric AMPHOTERICIN (B)
Mode of action Inhibit cell membrane synthesis, alter cell permeability, form complex with ergosterol of fungi
VIII. UnclassifiedAntibiotics • CHLORAMPHENICOL • In meningitis, typhoid & paratyphoid fever. D-(-) threo-2-Dichloroacetamido --1-(4–nitrophenyl)-1,3-propanediol Thiamphenicol CH3SO2-