‫بسم الله الرحمن االرحيم‬

CELL WALL SYNTHESIS

INHIBITORS
.Pharmacology Seminar
.Group: A1
Names n their work.
 Structure of cell wall

By:
Dr. Ahmed Al-Mustafa.
Dr. Ahmed Izzeldin.
Bacterial structure
We have three layer of the bacterial cell:

1. Cell wall.
2. Capsule.
3. Plasma membrane.
Types of bacterial cell wall:
According to the position of peptidoglycan layer in the cell wall bacteria are
classified into two types:
1. Gram positive bacteria.
2. Gram negative bacteria.
Gram positive vs Gram negative
Gram positive Gram negative
 Mechanism of action of penicillin’s

By:
Dr. Abrar Abd Al-fattah Ahmed.
Dr. Aufomia Akram.
• The general principle is that penicillin interfere with last step in bacterial cell wall
synthesis.
• Resulting in osmotically less stable membrane.
• Penicillin acts on rapidly growing organisms that synthesize a peptidoglycan cell
wall.
• Consequently, they are inactive against organisms devoid of this structure.
Penicillins act by:
1-Inhbition of cell wall synthesis.
2-Destruction the existing cell wall.
 Inhibition of cell wall synthesis.

This is achieved by acting on:

1.Penicillin binding proteins “PBPs”.
2.Inhibition of transpeptidases.
• The PBPs are bacterial enzymes involved in the synthesis of cell wall and in
maintenance of the morphological features of the bacterium; so exposure to
these antibiotics will prevent the cell wall synthesis and morphological
changes or lysis of bacteria.
• The transpeptidases are enzymes that catalyze the formation of cross linkage
between peptidoglycan that is responsible from the integrity of the bacterial cell
wall.
• By exposure to this type of antibiotics, the bacterial cell wall loss its integrity.
 Destruction of the existing cell wall.

• Autolysin produce normally by bacteria.

• So how can antibiotic affect them?
• Autolysin in absence of antibiotics.
• Found particularly in gram positive bacteria.
• Important in normal remodelling of the bacterial cell wall.
• Peptidoglycan matrix is very rigid ,so it degrade it into small sections for
further growth to occur.
• It degrade NAG-NAM bond.
• Autolysin in presence of antibiotics:-
• Degradative action of autolysin proceed in the absence of cell wall synthesis.
• Lysis in cell wall make it prone to rupture when found in low osmotic pressure
media
 Classification of penicillin

By:
Dr. Ahmed Saeed.
• Substituents of the 6-aminopenicillanic acid moiety determine the
essential pharmacologic and antibacterial properties of the resulting
molecules.
Penicillins can be classified into 3 groups based on
antibacterial spectrum:

1. Natural penicillins.
2. Antistaphylococcal penicillins.
3. Extended-spectrum penicillins (Aminopenicillins and Antipseudomonal
penicillins).
1. Natural penicillins:
They are Obtained Directly From the Penicillium mold and do not require further
modification.
E.g. penicillin G, penicillin V.
Penicillin G:
• Half life is short 30 mins - 1hour (Probenecid Prolong it’s half life How?)
• Sensitive to β-Lactamases.
• Route of administration: I.M or I.V.
• Eliminated by the kidney.
 Penicillin G is mainly used to treat infections with the following organisms (resistant
strains of bacteria are being isolated more frequently):

• Gram-positive cocci (aerobic): Pneumococci, streptococci (except S. faecalis), and

non-penicillinase-producing staphylococci.
• Gram-positive rods (aerobic): Bacillus species, also Clostridium perfringens, C.
diphtheriae, and Listeria spp., although the use of these agents is declining due to the
availability of better drugs.
• Gram-negative aerobes: Gonococci (non-penicillinase-producing) and meningococci
• Gram-negative rods (aerobic): None
• Anaerobes: Most, except Bacteroides fragilis. This agent is used against oral
anaerobes.
• Other: Treponema pallidum (syphilis) and Leptospira spp. These are common
pathogens for which first-generation penicillins are used today.
Penicillin V:
The oral form of penicillin.
is indicated only in minor infections because of:
1. Its relatively poor bioavailability
2. The need for dosing four times a day
3. Relatively to penicillin G , Penicillin V has narrow antibacterial spectrum.
 2. Antistaphylococcal penicillins

• E.g. (oxacillin, dicloxacillin, methicillin, and nafcillin)

• They are used predominantly for penicillinase-producing staphylococcal infections.
• They have very narrow spectrum why?
• All are relatively acid-stable and have reasonable bioavailability.
• Food interferes with their absorption.
• The use of these agents, which are administered orally, is declining due to the
increased incidence of methicillin-resistant S. aureus (MRSA).
• For example methicillin half life is 25-60 mins and its Route of administrations is IV
is more effective.
3. Extended-spectrum penicillins (aminopenicillins and the
antipseudomonal penicillins):

• They are inactivated by β-lactamases.

• These drugs retain the antibacterial spectrum of penicillin and have improved
activity against gram-negative organisms.
A) Aminopenicillins:
• Ampicillin. Ampicillin is useful for infections caused by Haemophilus influenzae,
Streptococcus pneumonia, Streptococcus pyrogens, Neisseria meningitidis, Proteus
mirabilis, and Enterococcus faecalis.
 Half life : 1-3 hours.
 Route of administration: IV or IM .
• Amoxicillin (Amoxil) is similar to ampicillin, but has better oral absorption.
Amoxicillin is commonly used for endocarditis prophylaxis before major procedures
.
 Route of administration: IV or IM .
B) Antipseudomonal penicillins (Carboxypenicillins, and
Ureidopenicillins):

• They are called antipseudomonal penicillins because of their activity against

Pseudomonas aeruginosa .
• The ureidopenicillins, piperacillin, mezlocillin, and azlocillin, are active against
selected gram-negative bacilli, such as Klebsiella pneumoniae.
• A carboxypenicillin (Piperacillin) has good activity against Pseudomonas spp.
and Enterobacter spp.
β- lactamase inhibitors
• β- lactamase inhibitors are structurally related to penicillin but has no antibacterial
properties of its own.
• The addition of a β-lactamase inhibitor to Ampicillin, amoxicillin, ticarcillin, and
piperacillin extends the activity of these penicillins to include β-lactamase-producing
strains of S aureus as well as some β-lactamase-producing gram-negative bacteria.
• E.g. clavulanic acid, sulbactam, or tazobactam.
 Bacterial resistance
to Antibiotics

By:
Dr. Ahmed Abdelghayoum.
1. What is antibiotic resistance?
2. How do bacteria become resistance to penicillin?
3. Transport of resistance by plasmids.
4. How to treat bacteria which is resistant to certain type of antibiotic?
• Antibiotic resistance is the ability of bacteria or other microbes to resist the
effects of an antibiotic.
• The resistance may be:
 Natural.
 Acquired.
Be obtaining resistance plasmid, bacteria may acquired:

1. B lactamase activity:
These enzymes hydrolyze the cyclic amide bond of B- lactam ring result in
loss of bactericidal activity.
2. Decrease permeability to the drug:
Due to the presence of an efflux pump that reduce the amount of intracellular
drug.
3. Altered penicillin binding proteins:
Modified PBPs have low affinity for B lactam antibiotic.

• Example: MRSA resistance to most commercially available B lactam.

 Pharmacokinetic of the
bacterial cell wall inhibitor
 Pharmacokinetic.

Involve:-
1. Administration and absorption.
2. Distribution
3. Metabolism
4. Excretion
1- Administration:
• Oral route.
• Intravenous.
• Intramuscular.
 penicillin cephalosporine
Oral route
intravenous
intramuscular
 The drug is administered based on:
• Severity of the infection.
• Stability of the drug in the gastric acid.
• Chemical features (solublity-ioniztion).
Note:-
For antibiotic that is administered orally, it must be given at least 2hours before
or after a meal.
 Absorption:
Movement of a drug from intestinal lumen through the mucosal lining to the
circulation.
 It depends on:
• Solubility.
• Ability of the antibiotic to ionize.
Note:
The absorption of the cell wall inhibitors is not
complete ,hence the remaining amount will affect the intestinal flora.
 Pharmacokinetics Metabolism

By:
Dr. Abdullah Abu-Baker.
• Drug metabolism (Xenobiotics metabolism) is the metabolic breakdown of drugs
by living organisms, usually through specialized enzymatic systems.
• Cytochrome P450 oxidases are important enzymes in xenobiotic metabolism.
 Drug metabolism is divided into three phases:

Phase I - Modification.
phase II - Conjugation.
phase III - Further modification and excretion.
 Phase I

In phase I, enzymes - such as cytochrome P450 oxidases introduce reactive or

polar groups into xenobiotics.
Phase I reactions (also termed no synthetic reactions) may occur by oxidation,
reduction, hydrolysis, cyclization, decyclization, carried out by mixed function
oxidases, often in the liver.
Cytochromes P450 (often abbreviated CYPs) are the major enzymes involved in
drug metabolism.
 Phase II

These modified compounds are then conjugated to polar compounds in phase II

reactions. These reactions are catalyzed by transferase enzymes such as
glutathione S-transferases.
Conjugation can be with charged species such as glutathione (GSH), sulfate,
glycine, or glucuronic acid.
 Phase III

Finally, in phase III, the conjugated xenobiotics may be further processed, before
being recognized by efflux transporters and pumped out of cells.
Drug metabolism often converts lipophilic compounds into hydrophilic products
that are more readily excreted.
 β-lactam antibiotics
   In general, Pharmacokinetics metabolism of β-lactam antibiotics is insignificant by
host.
 Penicillin
Host metabolism of the β-lactam antibiotics is usually insignificant.
But some metabolism of penicillin G may occur in patients with impaired renal
function.
CUBICIN (daptomycin for injection).
Metabolism:

• In vitro studies with human hepatocytes indicate that daptomycin does not inhibit
or induce the activities of the following human cytochrome P450 isoforms: 1A2,
2A6, 2C9, 2C19, 2D6, 2E1,  and 3A4.

• In in vitro studies, daptomycin was not metabolized by human liver microsomes. It

is unlikely that daptomycin will inhibit or induce the metabolism of drugs
metabolized by the P450 system.
• In 5 healthy young adults after infusion of radiolabeled 14 C-daptomycin, the
plasma total radioactivity was similar to the concentration determined by
microbiological assay.

• In a separate study, no metabolites were observed in plasma on Day 1 following

administration of CUBICIN at 6 mg/kg to subjects.

• Inactive metabolites have been detected in urine, as determined by the  difference in

total radioactive concentrations and microbiologically active concentrations.

• Minor amounts of three oxidative metabolites and one unidentified compound were
detected in urine.

• The site of metabolism has not been identified.

Penicillin side effect
Mild symptoms:

• Hives.
• Difficulty of breathing.
• Swelling of face, lips, tongue and d throat.
Moderate side effects:

• Nausea, vomiting, stomach pain.

• Vaginal itching or discharge.
• Headache.
• Black tongue.
• Thrush.
Serious side effects:

• Diarrhea (watery or bloody).

• Fever, chills, body aches, flu symptoms.
• Weakness.
• less urination or none!
• Severe skin rash ,itching or peeling.
• Seizure (black-out, convulsions ).
• Agitation, confusion, unusual thoughts.
Anaphylaxis:
Rare life threatening allergic reaction that causes a wide-spread dysfunction of body
systems.

 Cardinal features:
• Trouble of breathing.
• Nausea , abdominal cramps.
• Vomiting or diarrhea.
• Dizziness.
• Weak rapid pulse.
• Dropped BP.
• Loss of consciousness.
 Cephalosporins

By:
Dr. Abdulmalik Hatem.
Dr. Ahmed Hazeema.
Dr. Ahmed Khairy.
 Cephalosporins: are β-lactam antibiotics that have a bactericidal activity which
inhibit bacterial cell wall synthesis by inhibiting transpeptidase.

But this is the definition of penicillin isn’t it ?!

Difference between cephalosporins and penicillin

Cephalosporins and penicillins are two different families of antibiotics used to treat
different ailments. 

Cephalosporins are used to treat respiratory tract infections, otitis media, skin and
skin structure infections, bone infections, and genitourinary tract infections. 

Penicillins are used to treat mild to moderately severe infections due to penicillin G-
sensitive microorganisms. Penicillins have been prescribed to treat streptococcal
infections, pneumococci infections, staphylococcal infections, and fusospirochetosis
of the oropharynx. They have been used for a number of other ailments but those are
considered unlabeled uses.
Antibacterial spectrum
Cephalosporins are classified into five generations according to their bacterial
susceptibility patterns and resistance to β-Lactamase.

1. First generation
e.g. Cefalotin and Cefazolin.

2. Second generation.
e.g. Cefoxitin.
3. Third generation
e.g. Cefotaxime
4. Forth generation
e.g. Cefozopran
5. Advanced generation
e.g. Ceftolozane.
Resistance
Mechanisms of bacterial resistance to the cephalosporins are essentially the same as
those described for the penicillins.

[Note: Although they are not susceptible to hydrolysis by the staphylococcal

penicillinase, cephalosporins may be susceptible to ESBLs].

Organisms such as E. coli and K. pneumoniae are particularly associated with ESBLs.
Pharmacokinetics
Administration:

• Many of the cephalosporins must be administered IV or IM.

Distribution:

• All cephalosporins distribute very well into body fluids.

• However, adequate therapeutic levels in the CSF, regardless of inflammation, are
achieved with only a few cephalosporins.
• For example, ceftriaxone and cefotaxime are effective in the treatment of neonatal
and childhood meningitis caused by H. influenzae.
• Cefazolin is commonly used as a single prophylaxis dose prior to surgery because
of its 1.8-hour half-life and its activity against penicillinase-producing S. aureus.
• Cefazolin is effective for most surgical procedures, including orthopedic surgery
because of its ability to penetrate bone.
• All cephalosporins cross the placenta.
Elimination:
• Cephalosporins are eliminated through tubular secretion and/or glomerular
filtration.
• Therefore, doses must be adjusted in cases of renal dysfunction to guard against
accumulation and toxicity.
• One exception is ceftriaxone, which is excreted through the bile into the feces
and, therefore, is frequently employed in patients with renal insufficiency.
Adverse effects
• Like the penicillins, the cephalosporins are generally well tolerated.
• However, allergic reactions are a concern.
• Patients who have had an anaphylactic response, Stevens-Johnson syndrome, or toxic
epidermal necrolysis to penicillins should not receive cephalosporins.
• Cephalosporins should be avoided or used with caution in individuals with
penicillin allergy.
• Current data suggest that the cross-reactivity between penicillin and cephalosporins
is around 3% to 5% and is determined by the similarity in the side chain, not the β-
lactam structure.
• The highest rate of allergic cross-sensitivity is between penicillin and first-
generation cephalosporins
7
8
 Telavancin

By:
Prof. Adil Bakri.
Clinical Pharmacology.
 Telavancin

• Is lipoglycopeptide bacterial antibiotic that is a synthetic derivative of

vancomycin.
• Is an off-white to slightly colored amorphous powder.
• Its molecular weight is 1755.6.
• It is highly lipophilic and slightly soluble in water.
• Like vancomycin, telavancin inhibits bacterial cell wall synthesis.
 Telavancin

• It is alternative to vancomycin, daptomycin, linezolid in treating complicated

skin and skin structure infections caused by gram positive organisms (including
MRSA).
• It is also an agent of last choice for hospital-aquired and ventilator-associated
bacterial pneumonia when alternative treatments are not suitable.
The use of telavancin in clinical practice is limited by significant adverse effects, e.g.
1. Renal impairment.
2. Interaction with anticoagulation laboratory assays.
3. Risk of fetal harm in pregnant woman.
4. Interaction with medications that prolong the QT interval (e.g.
fluoroquinolones).
 Fosfomycin

By:
Dr. Ali Ahmed.
 Fosfomycin

• Use of Fosfomycin:
It’s used to treat urinary tract infection (UTI).
 • How to use Fosfomycin?

• Mix with 0.5 cup of cold water and drink it right away.
• Don’t take dry powder.
 What do you do if you miss a dose?

• Only one dose of Fosfomycin is needed.

• If you miss your dose take it as soon as you think about it.
 Polymyxins

By:
Dr. Abdullah Khalid.
 Polymyxins

• Polymyxins are antibiotics. Polymyxins B and E (also known as colistin) are used
in the treatment of Gram-negative bacterial infections.
• Produced in nature by Gram-positive bacteria.
 Medical use

• Polymyxin are relatively neurotoxic and nephrotoxic, so are usually used only
as a last resort if modern antibiotics are ineffective or are contraindicated.
Typical uses are for infections caused by strains of multiple drug-resistant.
• Polymyxins B are not absorbed from the gastrointestinal tract.
• administration, intravenously or by inhalation.
• They are also used externally as a cream or drops.
 Mechanism of action

After binding to lipopolysaccharide (LPS) in the outer membrane of Gram-

negative bacteria, polymyxins disrupt both the outer and inner membranes. The
hydrophobic tail is important in causing membrane damage, suggesting a
detergent-like mode of action.
Resistance

• Gram-negative bacteria can develop resistance to polymyxins through various

modifications of the LPS structure that inhibit the binding of polymyxins to LPS.
• Antibiotic resistance to this drug has been increasing, especially in southern China.
 Daptomycin

By:
Dr. Abdulazem Omer.
 Daptomycin

Definition:
Daptomycin is a lipopeptide antibiotic used in the treatment of systemic and life-
threatening infections caused by gram-positive organisms. It is a naturally
occurring compound found in the soil.
Its distinct mechanism of action makes it useful in treating infections caused by
multiple drug-resistant bacteria.
 Mechanism:

1. Daptomycin binds and inserts into the cell membrane.

2. Aggregates in the cell membrane.
3. Alters the shape of the cell membrane to form a hole in the cell, allowing ions in
and out of the cell easily.
 Clinical use:
indications:
Daptomycin is approved for use in adults for skin and skin structure infections caused by
Gram-positive infections. S. aureus bacteremia, and right-sided S. aureus endocarditis. It
binds avidly to pulmonary surfactant, so cannot be used in the treatment of pneumonia.
There seems to be a difference in working daptomycin on hematogenous pneumonia.
 Adverse effects:

Common adverse drug reactions associated with daptomycin therapy include:

• Cardiovascular: low blood pressure, high blood pressure, swelling.

• Central nervous system: insomnia.
• Dermatological: rash.
• Gastrointestinal: diarrhea, abdominal pain.
• Hematological: eosinophilia.
• Respiratory: dyspnea.
 ‫م بحمده تعالى‬

Thank you for attending our seminar.