Cell W all I nhibitors - PowerPoint Presentation

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Cell Wall Inhibitors Assistant Professor Dr. Naza M. Ali

Lec 324 Oct 2019

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Cell wallThe cell wall is a rigid outer layer, it completely surrounds the cytoplasmic membrane, maintaining the shape of the cell and preventing the cell lysis from high osmotic pressure.Cell wall is composed of a polymer called peptidoglycan that

consists of glycan units joined to each other by peptide cross-links.

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Cell Wall Inhibitors: Inhibitors of cell wall synthesis require actively Proliferating microorganisms mean they have little or

no effect on bacteria that are not growing and dividing.

I.

Penicillins

Penicillins

are classified as beta-lactam drugs

because of their

unique four-membered lactam ring

.

All have a

thiazolidine

ring (A) is attached to a beta-

lactam

ring (B) that carries a secondary amino group

RNH-

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A

B

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Penicillin are among the most widely effective antibiotics The least toxic drugs, but increased resistance has limited their use.They differ from one another in the R substituent attached to the 6-aminopenicillanic acid residue

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The nature of this side chain affects1.The antimicrobial spectrum, 2. Stability to stomach acid, 3. Susceptibility to bacterial degradative enzymes beta-lactamases.

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Mechanism of Action: Interfere with last step of bacterial cell wall synthesisThey are bactericidal

1.Penicillin-Binding Proteins 2. Inhibit of transpeptidase 3. Activation of autolytic enzyme

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Penicillin-Binding Proteins: Penicillins inactivate numerous proteins on the

bacterial cell membrane. These PBPs are bacterial enzymes involved in the

synthesis of the cell wall and in the maintenance

of

the morphologic features of the bacterium.

Exposure to these antibiotics can lead to

morphologic

changes or

lysis

of susceptible bacteria.

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2. Inhibit of transpeptidase: Some PBPs catalyze formation of the cross-linkages between peptidoglycan chains. Penicillins inhibit this transpeptidase-catalyzed reaction,

thus hindering the formation of cross-links essential for cell wall integrity.

As

a result of this blockade of cell wall synthesis

.

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3. Activation of autolytic enzyme: The gram-positive cocci, produce degradative enzymes (autolysins) that participate in the normal remodeling of the bacterial cell wall.

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Mechanism of resistance1. Beta-Lactamase activity:this family of enzymes hydrolyzes the cyclic amide bondof the beta-lactam ring, which results in loss ofbactericidal activity.

2. Decreased permeability to the drug:decreased penetration of the antibiotic through the

Outer cell

membrane prevents the drug from

reaching

the target

PBPs.

3.

Altered PBPs:

modified PBPs have a lower affinity for

beta-lactam antibiotic.

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Antibacterial spectrumNatural penicillins: are obtained from fermentations of the mold Penicillum

Penicillin G (benzylpenicillin) is the cornerstone of therapy

for

infections caused by

a

number

of

gram

-

positive

cocci

,

gram

-negative

cocci

,

gram

-positive bacilli,

spirochetes and

anaerobic.

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Penicillin G is susceptible to inactivation by Beta lactamases (penicillinases). Penicillin V has a spectrum similar to that of penicillin G and is more acid-stable than penicillin G.

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2. Antistaphylococcal penicillins: Methicillin Nafcillin Oxacillin Dicloxacillin

Are resistant to staphylococcal beta lactamases

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3. Extended-spectrum penicillins: (semisynthetic) Aminopenicillins ( Ampicillin , Amoxicillin )

Inactivated by beta lactamase

have

an antibacterial

spectrum

similar to that of

penicillin

G but are more effective

against

gram-negative bacilli.

Infections of

E.

coli

,

H.

influnzae

,

P

.

mirabilis,

S.

typhi

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Ampicillin is the drug of choice for the gram-positive bacillus Listeria monocytogenes.In the treatment of respiratory infectionsAmoxicillin used prophylactically by dentists for patients with abnormal

heart valves who are to undergo extensive oral surgery.

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4) Antipseudomonal penicillins Carboxypenicillins ( carbenicillin , ticarcillin)

Ureidopenicillin ( Piperacillin ) Are effective against P

.

aeruginosa

Susceptible to hydrolysis by Beta lactamase

Formulation with

bete

-lactamase inhibitors extends antimicrobial spectrum of these

antibiotics

to include

penicillinase

-producing organisms

have

synergistic action when used

with aminoglycoside

.

Must be administered IV or IM

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ClassificationSpectrumSusceptible Drug Name

Natural penicillins gram-positive

cocci

,

gram-negative

cocci

,

gram-positive bacilli, spirochetes

anaerobic

Susceptible to inactivation by lactamases

Penicillin G

Penicillin V

Antistaphylococcal

Staphylococcal

Resistant to

beta lactamase

Methicillin

Nafcillin

Oxacillin

Dicloxacillin

Extended-spectrum

similar to penicillin G more effective

gram-negative bacilli

Infections of

E.

coli

,

H.

influnzae

,

P.

mirabilis

,

S.

typhi

Inactivated by beta lactamase

Ampicillin Amoxicillin

Antipseudomonal

P

.

aeruginosa

Inactivated by beta lactamase

Carbenicillin

Ticarcillin

Piperacillin

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PharmacokineticsRoute of administration is determine -by the stability of the drug to gastric acid -by the severity of the infection

Oral, I.M, I.VDepot forms: Procaine penicillin G,

benzathine

penicillin

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Absorption Absorption of orally administered depending in part on their acid stability and protein binding. Dicloxacillin, ampicillin, and amoxicillin are acid-stable and relatively well absorbed, Absorption of most oral penicillins (amoxicillin being an exception) is impaired by food, and the drugs should be administered at least 1–2 hours before or after a meal.

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IV administration of penicillin G is preferred to the IM route because of irritation and local pain from IM injection of large doses.

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Distribution:They distribute wellAll penicillin's cross placental barrier (not teratogenic)

Penetration into certain sites ( bone or CSF) is insufficient for therapy unless these sites are inflamed

,

Penicillin

levels in the prostate are insufficient to be

effective against infections.

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Enhanced penetration of penicillin into the

cerebral spinal fluid (CSF) during inflammation.

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Excretion: By tubular secretion system and glomerular filtration.Patients with impaired renal function must have dosage regimens adjusted.

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Adverse ReactionHypersensitivity: due to its metabolite, penicilloic acid, which reacts with proteins and serves as a hapten to cause an immune reaction. 5% of patient have maculopapular rash with marked swelling of lips, tongue &

anaphylaxisDiarrhea: due to disruption of the normal balance of intestinal microorganisms, is a common problem. It occurs to a greater extent with those have extended antimicrobial spectrum.

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Nephritis: methicillin cause nephrotoxicity.Neurotoxicity if injected intrathecallyHematologic toxicitiesCation

toxicity: penicillins are administered as sodium or potassium salt.

Toxicities caused by large quantities of Na or K

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