Penicillin: An introduction, classification, mechanism, Structure, with its effect.

Penicillin

Structure-of-penicillin

Penicillin is the most important antibiotic that was first extracted from the mold Penicillium notatum. Subsequently, a mutant of a related mold, P.chrysogenum, was found to give the highest yield of penicillin and is employed for the commercial production of this antibiotic. It is belonging to a group of antibiotics called Beta-lactam antibiotics.

Penicillin was discovered by chance in 1928. Alexander Flemings (1929) found that a diffusible substance was elaborated by Penicillium mold which destroys staphylococcus on the culture plate, and named it “penicillin” but could not purify it.

Molecular formula– C16H18N2O4

Molecular weight– 334.4 g/mol

IUPAC Name– 3,3-dimethyl-7-oxo-6-[(2-phenyl acetyl) amino]-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid

Classification of penicillin-

-Natural penicillin-

Benzyl penicillin (penicillin G)

-Semi synthetic penicillin-

The acid-resistant alternative to penicillin G-

Phenoxy methyl penicillin (Penicillin V)

Penicillinase-resistant penicillin-

Methicillin, cloxacillin, Dicloxacillin

Extended-spectrum penicillin-

Aminopenicillins- Ampicillin, bacampicillin, Amoxicillin

Carboxypenicillins– Carbenicillin

Ureidopenicillins- Piperacillin, Mezlocillin

-β-lactam inhibitor-

Clavulanic acid, Sulbactam, Tazobactam

You may read- anti microbial agents.

Mechanism of penicillin-

The penicillin interferes with the enzymes involved in the synthesis of the bacterial cell wall.  Because eukaryotes do not have cell walls so, this is a particularly suitable and safe target for antimicrobial chemotherapy.  Thus, the beta-lactam antibiotics, as a group, are the most widely prescribed antibiotics. Penicillin binds to a number of receptor proteins, transpeptidases, and carboxypeptidases called penicillin-binding proteins (PBPs).  For penicillin, the different microorganisms vary in the affinity of their penicillin-binding proteins (PBPs).

Penicillin

Bind (PBP) on the cell wall of susceptible bacteria

Inhibits transpeptidation

Prevents peptidoglycan synthesis

Cell wall deficient forms spheroplasts & filamentous forms

Autolysis

Cell death (bactericidal action)

In addition, some organisms like- gram-positive bacteria, are particularly able to mutate with their penicillin-binding proteins (PBPs) to provide targets with significantly less affinity (resistance) for penicillin-binding.  Some of the PBPs are essential and are present in low amounts. Other PBPs are not essential, and thus, are fewer desirable targets for antibiotics.  Differences in the “activity” – that is, the amount of particular penicillin needed to kill an organism – are also related to the ability of the penicillin to go through the outer wall of a bacterium. This usually depends on the charge properties of the molecule and the affinity of that penicillin for PBPs involved in cell wall biosynthesis.

Pharmacokinetics of penicillin-

Absorption

The acidic environment within the intestinal tract is unfavorable for the absorption of penicillin. In the case of penicillin V, only one-third of an oral dose is absorbed under the best of conditions. Food decreases the absorption of the penicillinase-resistant penicillin dicloxacillin because as gastric emptying time increases, the drug is destroyed by stomach acid. Therefore, it should be taken on an empty stomach.  Conversely, amoxicillin is stable in acid and is readily absorbed from the gastrointestinal tract.

 Distribution

The beta-lactam antibiotics distribute well throughout the body.  All the penicillin’s cross the placental barrier, but none have been shown to have teratogenic effects. However, administration into bone or cerebrospinal fluid (CSF) is Inadequate for therapy unless these sites are inflamed. The level of Penicillin in the prostate is insufficient to be effective against the infections.

Metabolism

Host metabolism of the β-lactam antibiotics is usually insignificant, but some metabolism of penicillin G may occur in patients with impaired renal function. Nafcillin and oxacillin are exceptions to the rule and are primarily metabolized in the liver.

Excretion

For the excretion of penicillin, the primary route is through the organic acid (tubular) secretory system of the kidney as well as from glomerular filtration. Patients with impaired renal function must have dosage regimens adjusted.

Because nafcillin and oxacillin are primarily metabolized in the liver, they do not require dose adjustment for renal insufficiency. The penicillin is also excreted in breast milk.

Structure of penicillin-

Structure-of-penicillin

The basic structure of the penicillin consists of a core four-membered β-lactam ring, which is attached to a thiazolidine ring. These two rings constitute the fundamental nucleus of all the penicillin, that namely as 6-amino penicillanic-acid (6-APA) a variety of semi-synthetic penicillin are produced by altering the composition of the side chain attached to 6-APA nucleus. Both of the 6-APA nucleus and side chain are essential for the antibacterial activity of penicillin.

SAR of penicillin-

SAR(Structural-activity-relationship)-of-penicillin

Synthesis of penicillin-

Synthesis-of-penicillin

Natural penicillin-

Penicillin G is a narrow-spectrum antibiotic and its activity is primarily to gram-positive bacteria and a few others. It is obtained from the fermentation of the mold Penicillium chrysogenum. The Penicillin G is known as benzylpenicillin.

Activity against these microorganisms-

-Cocci- streptococci (except enterococci) staphylococcus aureus, (gram-negative cocci) Neisseria gonorrhea, N. meningitis.

-Bacilli– B.anthracis, Corynebacterium diphtheria, Clostridium tetani.

Actinomyces Israeli (moderately sensitive)

Gram-negative bacilli- E coli., proteus.

Pharmacokinetics of natural penicillin-

It is relatively unstable in acid and thus, the bioavailability is low. There is poor penetration into the cerebrospinal (CSF) unless inflammation is present. Active renal tubular secretion results in a short half-life. The orally administered dose of penicillin is about one-third that absorbed from the intestinal tract under favorable conditions.

The pH 2 of gastric juice rapidly destroys the antibiotics. From I.M site absorption is rapid and complete. Peak plasma levels attained in 30min.

SEMI SYNTHETIC PENICILLINS-

Semisynthetic penicillin is produced by chemically combining specific side chains (in place of the benzyl side chain of Penicillin G) or by incorporating specific precursors in the mold cultures. Thus, procaine penicillin and benzathine penicillin are salts of Penicillin G and not semi-synthetic penicillin.

The aim of producing semisynthetic penicillin has been to overcome the shortcomings of Penicillin G, which are-

-Poor oral efficacy.

-Susceptibility to penicillinase.

-Narrow spectrum of activity.

-Hypersensitivity reactions.

In addition, some beta-lactamase inhibitors have been developed which themselves are not antibacterial, but augment the activity of penicillin’s against beta-lactamase producing organisms.

PENICILLINASE-RESISTANT PENICILLINS-

This analog of penicillin has side chains that protect the beta-lactam ring from attack by staphylococcal penicillinase. However, this also partially protects the bacteria from the beta-lactam ring and non-penicillinase producing organisms are much less sensitive to these drugs than to Penicillin G.

Their only indication is about the infections caused by penicillinase-producing Staphylococci. For them, they are the perfect choice of drugs, except in areas where methicillin-resistant Staph. aureus (MRSA) has become prevalent. These drugs are not resistant to beta-lactamases produced by gram-negative bacteria. resistant—must be injected. It is also an inducer of penicillinase production. MRSA has emerged in many areas.

These are insensitive for all penicillinase-resistant penicillin’s (PRPs) and to other beta-lactams as well as to erythromycin, aminoglycosides, and tetracyclines, etc. The MRSA has altered PBPs which do not bind penicillin.

The drug of choice for these organisms is vancomycin/linezolid, but ciprofloxacin can also be used. Haematuria, albuminuria, and reversible interstitial nephritis are the specific adverse effects of methicillin. It has been replaced by cloxacillin.

Cloxacillin/Dicloxacillin-

 These are having the isoxazolyl side chain and highly penicillinase as well as acid-resistant. Activity against Penicillin G sensitive organisms is weaker, and it should not be used as a substitute for Penicillin G. These are more active than methicillin against penicillinase-producing Staph (PPS), but not against MRSA. Cloxacillin and dicloxacillin is incompletely but dependably absorbed from the oral route, especially if taken in an empty stomach.

Elimination occurs primarily by the kidney, also partly by the liver.

Structure of Cloxacillin-

Structure-of-cloxacillin

Structure of Dicloxacillin-

Structure-of-dicloxacillin

Properties and uses-

-It has good gram-positive potency against susceptible Staphylococci and Streptococci.

-Useful against some gram-positive cocci but not effective against gram-negative bacilli.

-Plasma t½ is about 1 hour.

-It is > 90% plasma protein-bound.

-EXTENDED SPECTRUM PENICILLINS-

This semisynthetic penicillin is active against a variety of gram-negative bacteria also. They can be grouped according to their spectrum of activity.

Aminopenicillins

The group of aminopenicillin is led by ampicillin, that it has an amino substitution in the side chain.  In aminopenicillin, some are prodrugs, and all they have quite similar antibacterial spectra. None of these are resistant to penicillinase or to the other beta-lactamases.

Ampicillin

Ampicillin is active against all the organisms that are sensitive to Penicillin G. In addition, many gram-negative bacilli, e.g. H. influenzae, E. coli, Proteus, Salmonella Shigella, and Helicobacter pylori are inhibited. However, due to wide-spread use, many of these have developed resistance and the usefulness of this antibiotic has decreased considerably.

Ampicillin is more active than Penicillin G for Strep. viridans, enterococci, and Listeria and equally active for pneumococci, gonococci, and meningococci (penicillin-resistant strains are resistant to ampicillin as well), but less active against other gram-positive cocci. Penicillinase-producing Staph. (PPS) are not affected, like- other gram-negative bacilli, such as Pseudomonas, Klebsiella, indole positive Proteus, and anaerobes like Bacteroides fragilis.

– The corresponding product from acylation with 2-azido-4-hydroxyphenyl acetyl chloride is amoxicillin. – the α-amino group plays an important role in the broader activity.

Structure of ampicillin-

Structure-of-ampicillin

Properties and uses-

-It is a white hygroscopic powder.

-It is freely soluble in water, sparingly soluble in acetone, but practically insoluble in fatty oils, and liquid paraffin.

 – Used to treat urinary tract infections and respiratory tract infections.

-The protonated α-amino group of ampicillin has a pKa of 7.3 and is thus extensively protonated in acidic media, which explains ampicillin’s stability towards acid hydrolysis and instability towards alkaline hydrolysis.

Bacampicillin

It is an ester prodrug of ampicillin which is nearly completely absorbed from the gastrointestinal tract and is primarily hydrolyzed during absorption. Thus, higher plasma levels are attained. The incidence of diarrhea is claimed to be lower, because of lesser alteration in intestinal ecology. Primary excretion is the kidney, partly enterohepatic circulation occurs. The plasma half-life is 1hour.

Structure of bacampicillin-

Structure-of-bacampicillin

Properties and use-

-It is acid-resistant.

–Its oral absorption is incomplete but adequate.

-It is used in UTI, RTI, Meningitis, Gonorrhea, typhoid fever, bacillary dysentery, Cholecystitis, Subacute bacterial endocarditis, and Septicemias.

Amoxicillin

It is a close analog of ampicillin but not a prodrug, that is similar to it in all respects except- oral absorption is better, food does not interfere with absorption, higher and more sustained blood levels are produced. Many physicians now prefer it over ampicillin for bronchitis, urinary infections, SABE, and gonorrhea.

Structure of amoxicillin-

Structure-of-amoxicillin

Properties and use-

-The incidence of diarrhea is lower.

-It is less effective against Shigella and H. Influenzas.

-It is higher effective against penicillin-resistant Strepi pneumoniae.

-It is a component of most triple-drug H. pylori eradication regimens.

Carboxypenicillins

The special feature of this analog is its activity against Pseudomonas aeruginosa and indole positive Proteus which are not inhibited by Penicillin G or aminopenicillins.

Carbenicillin

Carbenicillin is less active against Salmonella, E.coli, and Enterobacter, while Klebsiella and gram-positive cocci are untouched by it. In carbenicillin, pseudomonas strains are less sensitive to it, that has developed in some areas, particularly when inadequate doses have been used. Carbenicillin is neither penicillinase-resistant nor acid-resistant. It is inactive orally and is excreted rapidly in urine and the t½ is 1 hour.

It differs from ampicillin by having an ionizable carboxyl group substituted on the alpha carbon atom of the benzyl side chain rather than an amino group.

At the higher doses of carbenicillin, enough sodium may be administered to cause fluid retention and CHF in patients with borderline renal or cardiac function, and also caused bleeding by interfering with platelet function.

Structure of carbenicillin-

Structure-of-carbenicillin

Properties and uses-

-It is a white to off white crystalline powder with a bitter taste.

-It is hygroscopic in nature, soluble in water or alcohol, insoluble in chloroform or ether.

– has low toxicity, except allergic sensitivity, and the drug interferes with platelet function resulting in bleeding.

-It is effective in the treatment of systemic and urinary tract infections.

Ureido penicillins

Piperacillin-

Piperacillin is antipseudomonal penicillin, which is about 8 times more active than carbenicillin. It has good activity against Klebsiella, many Enterobacteriaceae, and some Bacteroides. Elimination t½ is 1-hour Concurrent use of gentamicin or tobramycin is advised.

Structure of piperacillin-

Structure-of-piperacillin

Properties and use-

It is more potent among these extended-spectrum penicillin.

Piperacillin has good activity against Klebsiella.

 It is used mainly in neutropenic and immune-compromised patients having serious gram-negative infections and in burns.

Uses of penicillins –

-Streptococcus pneumoniae infections

-Meningococcal infections

-Syphilis

-Actinomycosis

-Trench mouth

-Prophylaxis against Group A Streptococci in patients with a history of rheumatic heart

Disease

Unit of Penicillins –

-The IU of penicillin is the specific activity contained in 0.6 micrograms of the crystalline sodium salt of penicillin G.

Thus 1g= 1.6 million units

1 million unit= 0.6g

Physical properties of penicillins –

It is an amorphous white powder.

It is odorless and inactivated in the presence of heat.

In the dry form, natural penicillin and their salts are stable for several years at room temperature.

It is sparingly soluble in water, insoluble in petroleum ether, and soluble in methanol, ethanol, ether, ethyl acetate, benzene, chloroform, acetone.

The adverse effect of penicillins-

rash

diarrhea

hives

hoarseness

wheezing

joint pain

abdominal pain

black, hairy tongue

difficulty swallowing or breathing

swelling of the throat, tongue, or lips

sore throat, a return of fever, chills, etc.

BETA-LACTAM INHIBITORS-

Beta-lactamases are a family of enzymes produced by many gram-positive and gram-negative bacteria that inactivate beta-lactam antibiotics by opening the beta-lactam ring. Different beta-lactamases differ in their substrate affinities. There are three inhibitors of this enzyme that are available for clinical use- clavulanic acid, sulbactam, and tazobactam.

Structure-of-beta-lactam-inhibitor

You may read- β-Lactam antibiotics.

Clavulanic acid-

It is obtained from Streptomyces clavuligerus. It has a beta-lactam ring but no antibacterial activity of its own. It inhibits a wide variety of Class II to Class V of beta-lactamase. It is a progressive inhibitor, binding with beta-lactamase is reversible initially but becomes covalent later – inhibition increasing with time. It is also known as a suicide inhibitor, it gets inactivated after binding to the enzyme. It has a rapid oral absorption with bioavailability is 60% and t ½ is 1 hour.

Uses

-The addition of clavulanic acid stabilizes the activity of amoxicillin against beta-lactamase-producing resistant Staph. Aureus, H. influenzas, N. Gonorrhoeae, E Coli proteus, klebsiella, salmonella, and bacteria Fragilis.

Co-amoxiclav is indicated for

-Odontogenic infection

-Skin and soft tissue infection.

-Respiratory tract infection.

-Intraabdominal and gynecological infection

Sulbactam

Sulbactam is a semisynthetic beta-lactamase inhibitor. It is related to chemically as well as in-activity to clavulanic acid. It is also a progressive inhibitor, that combined with ampicillin. On the weight basis, it is less potent than clavulanic acid for most type of enzymes, but the same level of inhibition it can be obtained at the higher concentration achieved clinically.  Oral absorption of sulbactam is inconsistent.  Therefore, it is preferably given parentally.

Tazobactam-

Tazobactam is similar to Sulbactam. The pharmacokinetics of tazobactam is matched with Piperacillin with which it is used for used in severe infections like peritonitis, pelvic, urinary, respiratory infections.  However, the combination is not effective against piperacillin resistant Pseudomonas.

These beta-lactam inhibitors are available only in fixed combinations with specific penicillin-

-Ampicillin + Sulbactam (1g+0.5g I.V/I.M injection)

-Amoxycillin + Clavulanic acid (250mg+125mg tab)

-Piperacillin + Tazobactam sodium (2g+0.25g I.V/I.M injection)

The adverse effect of beta-lactam inhibitors-

-As same as amoxicillin alone.

– Poor gastrointestinal tolerance (especially in children).

– Other side effects-

-Candida stomatitis.

-Vaginitis.

-Rashes. -some cases of hepatic injury have been reported.