Penicillin

Penicillin

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  ANTIBIOTICS DR. S. S.HARAK
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  INTRODUCTION • Antibiosis-process bywhich one organism destroys another to preserve itself by producing a metabolite & the metabolic substance is Antibiotic • Definition : A substance produced by microorganisms, which has capacity of inhibiting the growth or destroying other microorganisms at low concentrations without affecting host to a considerable extent.
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  INTRODUCTION A substance isclassified as an antibiotic if • It is a product of metabolism (although it may be duplicated or even have been anticipated by chemical synthesis). • It is a synthetic product produced as a structural analog of a naturally occurring antibiotic. • It antagonizes the growth or survival of one or more species of microorganisms. • It is effective in low concentrations.
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  HISTORY OF ANTIBIOTICS •500-600 BC molded curd of soyabean used to treat boils & carbuncles in Chinese folk medicine. • Moldy Cheese to treat wounds in Ukraine • 1877- Pasteur & Jobuert – anthrax bacilli killed in presence of certain bacteria • 1889 – Vuilemin coined termed antibiosis (against life) • 1929 – Alexander Fleming accidental discovery of antibacterial effects of penicillium. • 1938- florey & Chain brought Penicillin in Clinical practice • Waksman proposed defination of anitbiotics
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  CURRENT STATUS OFANTIBIOTICS • Commercial and scientific interest • Thousands isolated& identified antibiotic substances • Numerous semisynthetic and synthetic derivatives
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  CLASSIFICATION OF ANTIBIOTICSCellWallInhibitors Beta-Lactams
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  CLASSIFICATION OF ANTIBIOTICS
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  SELECTING A METABOLITEAS A ANTIBIOTIC In addition to the ability to combat infections or neoplastic disease, the antibiotic must possess • First, selective toxicity to be effective against pathogenic microorganisms/ neoplastic tissue, without causing significant toxic effects. • Second, chemically stable when isolated, processed, and stored for a reasonable length of time without deterioration of potency & then convereted to suitable dosage forms to provide active drug in vivo. • Third, biotransformation and elimination should be slow enough to allow a convenient dosing schedule, yet rapid and complete enough to facilitate removal of the drug and its metabolites from the body soon after administration has been discontinued. • Some groups of antibiotics, because of certain unique properties, have been designated for specialized uses, such as the treatment of tuberculosis(TB) or fungal infections or anticancer. • Also used in animal and plant disease too..
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  MECHANISMS OF ANTIBIOTIC ACTION Siteof action Antibiotic Process interrupted Type of Activity Cell wall Bacitracin Mucopeptide synthesis Bactericidal Cephalosporin Cell wall cross-linking Bactericidal Cycloserine Synthesis of cell wall peptides Bactericidal Penicillins Cell wall cross-linking Bactericidal Vancomycin Mucopeptide synthesis Bactericidal Cell membrane Amphotericin B Membrane function Fungicidal Nystatin Membrane function Fungicidal
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  MECHANISMS OF ANTIBIOTIC ACTION Siteof action Antibiotic Process interrupted Type of Activity Ribosomes 50S subunit Chloramphenic ol Protein synthesis Bacteriostatic Erythromycin Protein synthesis Bacteriostatic Lincomycins Protein synthesis Bacteriostatic 30S subunit Aminoglycosid es Protein synthesis and fidelity Bactericidal Tetracyclines Protein synthesis Bacteriostatic Nucleic acids Actinomycin DNA and mRNA synthesis Pancidal Griseofulvin Cell division, microtubule assembly Fungistatic
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  ΒETA-LACTAMS • Possess β-lactam(4-membered cyclic amide) ring structure are the dominant class of agents • Used for the chemotherapy of bacterial infections. • The 1st antibiotic to be used in therapy, penicillin (penicillin G), • Phenoxymethyl penicillin (penicillin V) biosynthetic are first choice for the treatment of infections caused by most species of Gram-positive bacteria. • Penicillins & cephalosporins are resistant to penicillinase- producing staphylococci and Gram-negative bacilli.
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  PENICILLIN CLASS DRUGS •Ampicillin • Amoxacillin • Bacampicillin • Benzylpenicillin • Carbenicillin and indanyl carbenicillin • Clavulanic acid • Methicillin • Mezlocillin and piperacillin • Nafcillin • Oxacillin, cloxacillin, and dicloxacillin • Phenoxymethyl penicillin • Piperacillin and tazobactam • Sulbactam • Ticarcillin
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  CEPHALOSPORIN CLASS DRUGS •Cefaclor • Cefadroxil • Cefamandole nafate • Cefazolin • Cefdinir • Cefditoren pivoxil • Cefotetan • Cefoxitin • Cefmetazole • Cefonicid • Cef triaxone • Cefuroxime • Cefoperazone • Cefotaxime • Cephalexin • Cephapirin • Cephradine • Loracarbef • Cefpodoxime proxetil • Cefprozil • Cef tazidime • Cef tibuten • Cef tizoxime • Cefepime • Cef ixime
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  OTHER CELL WALLINHIBITORS Carbapenems • Ertapenem • Imipenem • Meropenem Monobactams • Aztreonam Aminoglycosides Amikacin • Gentamicin • Kanamycin • Neomycin • Spectinomycin • Tobramycin
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  BETA LACTUM ANTIBIOTICS
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  BETA-LACTAM • A beta-lactam(β-lactam) ring is a four-membered lactam. • A lactam is a cyclic amide, and beta-lactams are named so because the nitrogen atom is attached to the β-carbon atom relative to the carbonyl. • The simplest β-lactam possible is 2-azetidinone.
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  TYPES OF LACTAM
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  BASIC RING NOMENCLATURE
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  NUMBERING SYSTEMS Two numbering systemsfor the fused bicyclic heterocyclic system exist. The Chemical Abstracts system initiates the numbering with the sulfur atom and assigns the ring nitrogen the 4-position. 4-thia-l- azabicyclo[3.2.0]heptanes, The numbering system adopted by the USP is the reverse of the Chemical Abstracts procedure, assigning number 1 to the nitrogen atom & number 4 to the
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  PENICILLIN GENERAL STRUCTURE
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  BASIC RING NOMENCLATURE
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  STRUCTURE OF PENICILLINS
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  STRUCTURE OF PENICILLINS
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  MECHANISM OF ACTION •Two properties contribute to the unequaled importance of β-lactam antibiotics in chemotherapy: 1. Potent and rapid bactericidal action against bacteria in the growth phase and 2. Very low frequency of toxic and other adverse reactions in the host. • The uniquely lethal antibacterial action of these agents has been attributed to a selective inhibition of bacterial cell wall synthesis. • Specifically, the basic mechanism involved is inhibition of the biosynthesis of the dipeptidoglycan that provides strength and rigidity to the cell wall.
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  MECHANISM OF ACTION •Penicillins and cephalosporins acylate a specific bacterial D- transpeptidase, thereby rendering it inactive for its role in forming peptide cross-links of two linear peptidoglycan strands by transpeptidation and loss of D-alanine. • Bacterial D-alanine carboxypeptidases are also inhibited by beta- lactam antibiotics.
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  MECHANISM OF ACTION •Penicillins and cephalosporins acylate a specific bacterial D-transpeptidase, thereby rendering it inactive for its role in forming peptide cross-links of two linear peptidoglycan strands by transpeptidation and loss of D-alanine. • Bacterial D-alanine carboxypeptidases are also inhibited by Beta-lactam antibiotics. • Binding studies with tritiated benzylpenicillin have shown that the mechanisms of action of various beta–lactam antibiotics are much more complex than previously assumed. • Studies in E. coli have revealed as many as seven different functional proteins, each with an important role incell wall biosynthesis.
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  PENICILLIN-BINDING PROTEINS (PBPS) FUNCTIONALPROPERTIES • PBPs 1a and 1b are transpeptidases involved in peptidoglycan synthesis associated with cell elongation. • Inhibition results in spheroplast formation and rapid cell lysis, caused by autolysins (bacterial enzymes that create nicks in the cell wall for attachment of new peptidoglycan units or for separation of daughter cells during cell division10). • PBP 2 is a transpeptidase involved in maintaining the rod shape of bacilli. • Inhibition results in ovoid or round forms that undergo delayed lysis. • PBP 3 is a transpeptidase required for septum formation during cell division. • Inhibition results in the formation of filamentous forms containing rod- shaped units that cannot separate. It is not yet clear whether inhibition of PBP 3 is lethal to the bacterium.
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  PENICILLIN-BINDING PROTEINS (PBPS) FUNCTIONALPROPERTIES • PBPs 4 through 6 are carboxypeptidases responsible for the hydrolysis of D-alanine–D-alanine terminal peptide bonds of the cross-linking peptides. • Inhibition of these enzymes is apparently not lethal to the bacterium,13 even though cleavage of the terminal D-alanine bond is required before peptide cross-linkage. • The various Beta-lactam antibiotics differ in their affinities for PBPs. • Penicillin G binds preferentially to PBP 3, whereas • the first-generation cephalosporins bind with higher affinity to PBP 1a. • In contrast to other penicillins and to cephalosporins, which can bind to PBPs 1, 2, and 3, amdinocillin binds only to PBP 2
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  CROSS-LINKING OF THE PEPTIDOGLYCANBY TRANSPEPTIDASES
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  CROSS-LINKING OF THE PEPTIDOGLYCANBY TRANSPEPTIDASES
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  INTERVENTION BY BETA-LACTAMANTIBIOTICS
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  SHAPE OF PENICILLING
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  DISTANCE THRESHOLD FOR ANTIBACTERIALACTIVITY
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  PENICILLIN SAR No Substitution allowed Sulphuris required but not mandatory Thiazolidine ring, essential for activity Carboxylic Acid: Involved in ionic interactions with N of lysine at binding site Activity ↓ if reduced by - COOR or -CHOH Trans - stereochemistry is required with COOH Acylamino sidechain: EWG make amide less Nucleophilic, Bulky gr provides steric hindrance to β-lactamase Polar grs make it more hydrophobic Carbonyl Group: Lone pair e- of N do not resonate to carbonyl group hence is venerable to nucleophilic attack Bicyclic system : Puts a strain on the β-lactam ring Strain directly proportional to instability of the structure β-lactam strained ring Dimethyl group: Essential, removal ↓activity
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  ΒETA-LACTAM CARBONYL - ELECTROPHILICSITE
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  SAR • Position 1– When the sulfur atom of the Thiazolidine ring is oxidized to a sulfone or sulfoxide, it improves acid stability, but decreases the activity of the agent. It is replaceable as in case with Carbapenems • Position 2 – No substitutions allow at this position, any change will lower activity. The methyl groups are necessary • Position 3 – The carboxylic acid of the Thiazolidine is required for activity. It ionizes & the has ionic interactions with a lysine moiety at receptor site increase the affinity towards the macromolecule. If it is changed to an alcohol or ester, activity is decreased. • Position 4 – The nitrogen is a must. • Position 5 – No substitutions allowed.
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  SAR • Position 7– The carbonyl on the Beta-lactam ring is a must. • Position 6 – Substitutions are allowed on the side chain of the amide. • An electron withdrawing group added at this position will give the compound better acid stability because this substitution will make the amide oxygen less nucleophillic. • A bulky group added close to the ring will make the compound more resistant to Beta-lactamases. • Steric hindrance provides protect to the Beta-lactam ring.
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  Β-LACTAM RING OPENINGBY ACYLAMINO SIDE-CHAIN • the acylamino side-chain can help aid the ring-opening of the β- lactam ring. • It can act as an internal nucleophile and attack the β-lactam carbonyl forming a very strained intermediate that then opens to break the β- lactam ring. • This makes the penicillin inactive and is sometimes described as a ‘self-destruct’ mechanism.
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  MODIFICATION OF ACYLAMINOSIDE- CHAIN • Placing an electron-withdrawing substituent(EWS) within the side- chain reduces nucleophilicity of acyl carbonyl • The EWS group accepts electrons & makes the amide carbonyl group a weaker nucleophile, which is less likely to react with the β- lactam carbonyl. • For example, penicillin G is more prone to ‘self-destruct’ than penicillin V, or phenoxymethylpenicillin.
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  PENICILLIN STEREOCHEMISTRY • C5& C6 –H should have cis orientation. • C6 –NH2 & C2 –COOH should have trans orientation. • Change in orientation increases instability & hence reduces activity.
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  AcylSide Chain Modifications
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  CHEMICAL INSTABILITIES Instability of β-lactamsto nucleophiles Solutions of penicillin's for parenteral use should be refrigerated, used promptly, and not stored
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  INSTABILITY OF PENICILLIN'S IN ACID. Hydrolysis involvesthe C-6 side chain.
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  BETA-LACTAMASE–CATALYZED HYDROLYSIS OF PENICILLINS
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  Β-LACTAMASE RESISTANT/SENSITIVE STRUCTURAL FEATURES •When the aromatic ring is attached directly to the side chain carbonyl and both ortho-positions are substituted by methoxy groups,b-lactamase stability results • Movement of one of the methoxy groups to the para position or replacing one of them with a hydrogen results in an analog sensitive to beta-lactamases. • Putting in a methylene between the aromatic ring and 6-APA likewise produces a b-lactamase–sensitive agent
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  Β-LACTAMASE RESISTANT/SENSITIVE STRUCTURAL FEATURES •Stability of the penicillins toward β-lactamase is influenced by the bulk in the acyl group attached to the primary amine. • β-Lactamases are much less tolerant to the presence of steric hindrance near the side-chain amide bond than are the penicillin binding proteins(PBPs). • When the aromatic ring is attached directly to the side-chain carbonyl and both ortho-positions are substituted by methoxy groups, β-lactamase stability results
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  BETA-LACTAMASE RESISTANT/SENSITIVE STRUCTURAL FEATURES • Movementof one of the methoxy groups to the para-position, or replacing one of them by a hydrogen, resulted in an analogue sensitive to β-lactamases. • Putting in a methylene between the aromatic ring and 6-APA likewise produced a β-lactamase–sensitive agent. • These findings provide strong support for the hypothesis that its resistance to enzyme degradation is based on differential steric hindrance. • Prime examples of this effect are seen in the drugs methicillin, nafcillin,
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  BENZYLPENICILLIN/ PENICILLIN G • (2S,5R,6R)-3,3-dimethyl-7-oxo-6-(phenylacetamido)-4-thia-1- azabicyclo[3.2.0]heptane-2-carboxylicacid • Has narrow spectrum of activity: active against Gram+ve bacilli (not producing β-lactamase) and Gram-ve cocci. • No serious side effects • Acid-sensitive (cannot be taken orally) • Sensitive to β-lactamase • May cause allergy to some patients. • All Psudomonas aeruginosa strains (Gram-ve) and some Staphyllococcus aureus (Gram+ve) strains are resistant.
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  PENICILLINASE- RESISTANT PENICILLINS
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  PHENOXYMETHYLPENICILLIN/ PENICILLIN V • (2S,5R,6R)-3,3-dimethyl-7-oxo-6-(2-phenoxyacetamido)-4-thi a-1-azabicyclo(3.2.0)heptane-2-carboxylic acid • 6-phenoxyacetamidopenicillanic acid • Less active than Penicillin G. • No serious side effects • Acid-stable • Sensitive to β-lactamase • May cause allergy to some patients.
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  METHICILLIN • Methicillin isthe first of the penicillinase-resistant agents to reach the clinic. • It is unstable to gastric acid, having a half- life of 5 minutes at pH 2, so it has to be administer via injection. • Increased bulk resulting from the addition of the dimethoxybenzoyl group to 6-APA leads to methicillin being a b-lactamase–resistant drug. • Methicillin has significantly narrower antimicrobial spectrum and less potency.
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  METHICILLIN • Substitutions atthe ortho positions of a phenylring increase the steric hindrance of the acyl group and confer more beta-lactamase resistance than shown by the unsubstituted compounds or those substituted at positions more distant from the alpha-carbon. • Bulkier substituents are required to confer effective beta-lactamase resistance among five-membered–ring heterocyclic derivatives • Clinical use primarily for parenteral use in infections due to b-lactamase producing S. aureus and a few other infections. • An increasing number of infections are caused by MRSA. • In these organisms, an altered PBP is formed that has a very low affi nity for beta-lactams, excluding ceftaroline. • Furthermore, methicillin is an efficient inducer of penicillinases. • Consequently this drug fell out of favor, and methicillin has now been replaced.
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  NAFCILLIN • Nafcillin hasa 2-ethoxynaphthylside chain. • This bulky group serves to inhibit destruction by b- lactamases analogous to methicillin. • Although slightly more acid stable than methicillin, it is clinically virtually identical to it.
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  OXACILLIN & DICLOXACILLIN •Using a substituted isoxazolyl ring as a bioisosteric replacement for the benzene ring of penicillin G produces the isoxazolyl penicillins. • Chemically, they differ from one another by chlorine substituents on the benzene ring. • Like methicillin, these are generally less potent than benzylpenicillin against gram-positive microorganisms (generally staphylococci and streptococci) that do not produce a b-lactamase but retain their potency against those that do. • They are more acid stable; thus they may be taken orally, and they are more potent as well.
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  OXACILLIN & DICLOXACILLIN •Because they are highly serum protein bound, they are not good choices for treatment of septicemia. • Microorganisms resistant against methicillin are also resistant to the isoxazolyl group of penicillins. • Like nafcillin, the isoxazolyl group of penicillins is primarily used against penicillinase-producing Staphylococcus aureus
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  PENICILLINASE-SENSITIVE, BROAD-SPECTRUM, ORAL PENICILLINS
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  AMPICILLIN • One ofthe hydrogen atoms of the side chain methylene has been replaced with a primary amino group to produce an R-phenylglycine moiety . • Significant acid stability - oral use. • Gram-negative pathogens are sensitive to ampicillin. • Greater penetration of ampicillin into gram negative bacteria. • The acid stability is due to electron-withdrawing character of the protonated primary amine group reducing participation in hydrolysis of the b-lactam bond as well as to the comparative difficulty of bringing another positively charged species (H3O+) into the vicinity of the protonated amino group. • The oral activity is also enhanced, in part, to active uptake by the dipeptide transporters. • It unfortunately lacks stability toward b-lactamases, and resistance is increasingly common.
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  BACAMPICILLIN • Prodrug • Itis a weak base and is very well absorbed in the duodenum. • Enzymatic ester hydrolysis in the gut wall liberates carbon dioxide and ethanol followed by spontaneous loss of acetaldehyde and production of ampicillin. • The acetaldehyde is metabolized oxidatively by alcohol dehydrogenase to produce acetic acid, which joins the normal metabolic pool. • Amoxicillin, which has better oral availability than ampicillin has made the reduced use of bacampicillin.
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  AMOXICILLIN • Close analogof ampicillin • para-phenolic hydroxyl group in the side-chain phenyl moiety. • The isoelectric point of the drug to a more acidic value and has enhanced blood levels as compared with ampicillin. • Better oral absorption leads to less disturbance of the normal GI flora and, therefore, less drug-induced diarrhea. • The antimicrobial spectrum similar to ampicillin. • Coadministered with clavulanic acid combination (Augmentin) in which the clavulanic acid serves to protect amoxicillin to a considerable extent against b-lactamases. • This expands the spectrum of activity to include organisms and strains that produce b-lactamases.
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  CARBENICILLIN • Semisynthetic Penicillin(1970), • It has an ionizable carboxyl group substituted on the alpha- carbon atom of the benzyl side chain. • Broad range of antimicrobial activity b’coz of the unique carboxyl group. • The carboxyl group improves penetration of the molecule through cell wall barriers of Gram-negative bacilli, compared with other penicillins. • Carbenicillin is not stable in acids and is inactivated by penicillinase. • It is a malonic acid derivative and decarboxylates readily to penicillin G, which is acid labile.
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  CARBENICILLIN • Effective inthe treatment of systemic & UTI caused by P. aeruginosa, indole-producing Proteus spp., and Providencia spp., all of which are resistant to ampicillin. • The low toxicity permits the use of large dosages in serious infections. • A combination of carbenicillin and gentamicin is for serious pseudomonal and mixed coliform infections. The two antibiotics are chemically incompatible, however, and should never be combined in an intravenous solution.
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  TICARCILLIN • Ticarcillin disodium,2-carboxy-3-thienylpenicillin (Ticar), is an isostere of carbenicillin in which the phenyl group is replaced by a thienyl group. • This semisynthetic penicillin derivative, unstable in acid, administered parenterally. • It is similar to carbenicillin in antibacterial spectrum & pharmacokinetic properties. • Two advantages for ticarcillin are clamied: (a) slightly better pharmacokinetic properties, including higher serum levels and a longer duration of action; and (b) greater in vitro potency against several species of Gramnegative bacilli, most notably P. aeruginosa and Bacteroides fragilis. • These advantages can be crucial in the treatment of serious infections requiring high-dose therapy.
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  MEZLOCILLIN • Acylureidopenicillin spectrumsimilar to that of carbenicillin and ticarcillin; however, there are some major differences. • It is much more active against most Klebsiella spp., P. aeruginosa, anaerobic bacteria (e.g., Streptococcus faecalis and B. fragilis), and H. influenzae. • It is recommended for the treatment of serious infections caused by these organisms.
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  PIPERACILLIN • Most usefulof the extended-spectrum acylureidopenicillins. • It is more active than mezlocillin against susceptible strains of Gram- negative aerobic bacilli, such as Serratia marcescens, Proteus, Enterobacter, Citrobacter spp., and P. aeruginosa. • Mezlocillin, however, appears to be more active against Providencia spp. and K. pneumoniae. • Piperacillin is also active against anaerobic bacteria, especially B. fragilis and S. faecalis (enterococcus). • Beta-Lactamase–producing strains of these organisms are, however, resistant to piperacillin, which is hydrolyzed by S. aureus beta-lactamase. • The Beta- lactamase susceptibility of piperacillin is not absolute because Beta- lactamase–producing, ampicillin-resistant strains of N. gonorrhoeae and H. influenzae are susceptible to piperacillin.
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  PROTEIN BINDING OFPENICILLINS • Penicillin % Protein binding • Benzyl penicill in 45 – 68% • Phenoxymethyl penicillin 75 – 89% • Methicillin 35 – 80% • Ampicillin 25 – 30% • Amoxicillin 25 – 30% • Carbenicillin ~50% • Oxacillin >90% • Cloxacillin >90%