Bacteria cell wall inhibitor Antibiotics (penicillins)

 Bacteria cell wall inhibitor Antibiotics | Penicillins |Dr Najeeb Lecture notes (pharmacology)

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Bacteria cell wall inhibitor Antibiotics includes:

These includes:

1) cycloserine

2) Bacitracin

3) Vancomycin

4) Beta-Lactam: They have beta lactam ring that bind with Penicillin Binding Proteins(PBPs). Beta lactamases destroy this ring resulting in resistance to these drugs. e.g. penicillin , cephalosporin , Carbapanem, Aztreonam.

Before discussing about drugs we must know about synthesis of Cell wall.

Synthesis of Cell wall

1)N-acetyl mucramic acid (NAM) and N-Acetylglucosamine (NAG) are synthesized first

2)They're then activated by adding UDP.

3)After that there is addition of pentapeptide to NAM 

4-a) And then these precursor molecules that are polar transported out of plasma membrane by BPP (Bactoprenol phosphate, non Polar) .

4-b) BPP accepts NAM and NAG and remove the UDP thus forming bond b/w NAM And NAG and peptidoglycan's monomer is formed. 

4-c) After that BPP flipped out thus transporting NAM-NAG outside.

5) Outside the NAM-NAG unit combine with other NAM-NAG units by a process called Glycosylation.(done by an enzyme)

6) peptide side chains of NAM are also cross linked with adjacent peptide side chain of NAM -NAG layer by process called transpeptidation .

7) There are enzymes called autolysins that help bacteria to replace the cell wall with new monomers to produce modification in cell wall It actually cuts the Polymer chain. But there are inhibitor to control the activity of autolysins. Penicillin can bind to autolysins inhibitors also, so autolysins are not under the control and they cause degradation of cell wall.

Action of drugs: 

i) Cycloserine hinders attachment of pentapeptide to NAM (step 3 is disrupted)

iI) Bacitracin : it prevent BPP to flip itself, so no more units can come out.( Step 4c)

iii) Vancomycin: it inhibit the enzyme that carry out Glycosylation (step 5).

iv) Beta-lactum (Penicillin, cephalosporins ,++) : inhibition of transpeptidation.

v) Penicillin: can bind to autolysins inhibitors also, so autolysins are not under the control and they cause degradation of cell wall.(step 7) 

Antibacterial spectrum of Penicillins:

The antibacterial spectrum of the various penicillins Is determined, in part, by their ability to cross the bacterial peptidoglycan cell wall to reach the PBPs (Penicillin Binding protein) in the periplasmic space. Factors determining PBP susceptibility to these antibiotics include size, charge, and hydrophobicity of the particular beta lactam antibiotic. In general, gram-positive microorganisms have cell walls that are easily traversed by penicillins, and therefore, in the absence of resistance, they are susceptible to these drugs. Gram-negative microorganisms have an outer lipopolysaccharide membrane surrounding the cell wall that presents a barrier to the water-soluble penicillins. However, gram-negative bacteria have proteins inserted in the lipopolysaccharide layer that act as water-filled channels (called porins) to permit transmembrane entry.

Now we will go a bit detail in Penicillin (beta lactum) 

Mechanism of action of Penicillin: 

Penicillins interfere with the last step of bacterial cell wall synthesis, which Is the cross-linking of adjacent peptidoglycan strands by a process known as transpeptidation.

penicillin-binding proteins (PBPs) aka transpeptidase catalyse transpeptidation and facilitate cross-linking of the cell wall.

Since penicillins structurally resemble the terminal portion of the peptidoglycan strand, they compete for and bind to PBPs , which results in the formation of a weakened cell wall and ultimately cell death.

 . For this reason, penicillins are regarded as bactericidal and work in a time-dependent fashion. Comparison of Cell wall is shown in the Table below:

Classification of Penicillins:

Penicillin are divided into:

1) narrow spectrum : i) natural penicillin (penicillin G and penicillin V) ii)  narrowest spectrum (anti staphylococcal penicillin) 

2) Wide spectrum : i) Extended Spectrum Penicillin ii) Anti-pseudonomal Penicillin

(i) Natural penicillin: 

-->Penicillin G and V.

They are mild bulky , can easily go to receptors of gram + but can't through gram negative porin. It works against G+ cocci, G+bacilli , G- Cocci (beacuse their porins are relatively wide) and spirochetes (tyrponema pallidum) but fails on G- baccili. Penicillin V is acid stable (due to heavy R group that protects beta lactum ring from acids) so it is taken orally i.e children suspected to rheumatic fever , mixed dental infections. 

(ii) Very very narrow spectrum penicillin (antistaphylococcal penicillin): 

very heavy molecule so spectrum is very narrow, mainly act on staphylococcal sp. 

These species have developed resistance to other penicillin by producing penicilinases that attack on beta lactum ring to cut it.

E.g methacillin (not clinically used now, because it causes interstitial nephritis) , nafcillin (safer but can also cause nephritis and neutropenia ) , oxacillin , dicloxacillin , cloxacillin , flucloxacilin.

Semisynthetic Penicillin (extended spectrum Penicillin) : 

Ampicillin [am-pi-SILL-in] and amoxicillin [a-mox-i-SILL -in] (also known as aminopenicillins or extended spectrum penicillins) are created by chemically attaching different R groups to the 6-aminopenicillanic acid nucleus. Addition of R

groups extends the gram-negative antimicrobial activity.

These drugs are smart like models and have less light R rings and base of beta lactum ring is exposed so they are vulnerable to penicilinases/Beta-Lactumases. So we add clavulanic acid , sulbactum or tazobactum that inbitits beta lactamases. Used Against: 

HELPS to clear Enterococci.

H: Haemophilus influenzae

E: E.coli

L: Listeria monocytogenes 

Note: Listeria monocytogenes is gram positive,  it is the only one gram+ that have little endotoxicity , otherwise practically all gram- have endotoxins: (lipopolysaccharide in their outer wall) 

P: Proteus mirabilis

S: Salmonella & Enterococci.

Anti-pseudonomal Penicillin(super smart / supermodels) : 

very Broad spectrum , it act on gram negative including Pseudomonas.

Piperacillin [pip-er-a-SILL-in] is also referred to as an antipseudomonal penicillin because of its activity against Pseudomonas aeruginosa. Formulation of piperacillin with *tazobactam* extends the antimicrobial spectrum to include penicillinase-producing organisms (for example, most Enterobacteriaceae and Bacteroides species.)

Extra information:

Bacteriocidal: effective in immuno suppressed person. These drugs can eliminate micbros even in the absence of Effective host immune defences.

bacteriostatic : they inhibit the growth of bacteria , but your immune system has to eliminate all the bacteria. It is only effective in person with effective immune response. e.g Penicillin, cephalosporins, aminoglcosides , Vancomycin , Flouroquinalones and Metronidazole ( mnemonic : Penicillin and Cephalosporins Are Very Cidal For Microbes).

Mechanism of Resistance:

1)Beta-Lactumases

2)Decreased permiabilty to pass through porins(they become narrow)

3) efflux pump ( throw the antibiotics out) 

4) change PBPs and Penicillin can't bind.(MRSA: methacyline resistant staphylococcus aureus,now this resistance is also present in streptococcus pneumoniae) Vancomycin is effective in this case.

Pharmacokinetics of Penicillins:

ONLY Orally:

 i) Penicillin V

 ii) amoxicillin

iii) amoxicillin + cluvanic acid

iv) indanyl Carbenicillin(special form of Carbenicillin)

Intravenous:

Anti-pseudonomal : ticarcilinin , Carbenicillin, piperacillin

Ampicillin with sulbactum is available in IV.

Depot Form:

Procane Penicillin

Benzathine with Penicillin

GIT absorption:

Amoxicillin has better GIT absorption so it is used for treatment of systemic infection, but not good for intestines.

Ampicillin is poorly absorbed, that's why it stays longer in GIT , so it is used to treate GIT infection.it is used as IV for systemic function and as tablet for GIT infection.

Anti-Staphylococcal Penicillin like: methacyline, nafcillin etc must be given 1hour before meal or after meal.

Distribution:

Due to polar nature they are not lipid soluble therefore they can't enter into the cells. They effectively kills bacteria that are extracellular.they are well distributed in extracellular fluids.

Normally the Penicillins doesn't cross the blood brain barrier but during encephalitis or meningitis the barrier is destroyed and they can act when there is need.

Penicillins go out mainly through urine, but nafcillin through liver. They are freely filtered into bowman's capsule as well as Actively transported (90%) into to lumen of nephron by organic acid secretory pumps.

If we give another drug with Penicillin that has more affinity to use these pumps then the Penicillins will not get chance to go to lumen hence its half-life will be increased, the drug is called Probenacid.

Note: aminoglcosides are used along with Penicillin to achieve more effective bacteriocidal effect during complex infections. It is because penicillin provide ease for aminoglcosides to be pumped actively into the cytosol , by weaking the cell wall of bacteria. These two drugs must not be put in same container.

Adverse Effects of Penicillins:

-Penicillin can cause hypersensitivity reactions (type 1,2,3) , its metabolites can't activate immune system own there own but when they are attached with Human proteins can activate it. e.g. penicillin mediated anaphylactic shock(type 1), Penicillin mediated hemolytic anemia(type 2) , type3 delayed: immune complexes are formed that deposited in different tissues:

[vasculitis(rashes), Glomerulonephritis , polyarthritis, pericarditis, pleuritis, generalized lymphadenopathy and fever]

-maculo-papular skin rashes are toxin reaction to skin not hypersensitivity. If a person is infected with Epstein–Barr virus (EBV), then if you give Penicillin patients will definitely develop maculopapular skin rashes.

-pseudomembranous colitis: due to dysbacteriosis.

-nephritis: methacillin, nafcillin (less often).

-platelet dysfunction (reduce aggregation).

-neutropenia

-cation toxicity ( it is Given with Sodium/potassium salts, Sodium concentration increase in blood and water is retained.)