Assistant Professor Dr Naza M Ali Lec 3 24 Oct 2019 Cell wall The cell wall is a rigid outer layer it completely surrounds the cytoplasmic membrane maintaining the shape of the cell ID: 805261
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Slide1
Cell Wall Inhibitors Assistant Professor Dr. Naza M. Ali
Lec 324 Oct 2019
Slide2Cell 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.
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-
A
B
Slide5Penicillin 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
Slide6The nature of this side chain affects1.The antimicrobial spectrum, 2. Stability to stomach acid, 3. Susceptibility to bacterial degradative enzymes beta-lactamases.
Slide7Mechanism 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
Slide8Slide9Penicillin-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.
Slide102. 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
.
Slide11Slide123. Activation of autolytic enzyme: The gram-positive cocci, produce degradative enzymes (autolysins) that participate in the normal remodeling of the bacterial cell wall.
Slide13Mechanism 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.
Slide14Antibacterial 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.
Slide15Penicillin 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.
Slide16Slide172. Antistaphylococcal penicillins: Methicillin Nafcillin Oxacillin Dicloxacillin
Are resistant to staphylococcal beta lactamases
Slide183. 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
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.
Slide20Slide214) 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
Slide22ClassificationSpectrumSusceptible 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
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
Slide24Absorption 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.
Slide25IV administration of penicillin G is preferred to the IM route because of irritation and local pain from IM injection of large doses.
Slide26Distribution: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.
Slide27Enhanced penetration of penicillin into the
cerebral spinal fluid (CSF) during inflammation.
Slide28Excretion: By tubular secretion system and glomerular filtration.Patients with impaired renal function must have dosage regimens adjusted.
Slide29Adverse 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.
Slide30Nephritis: 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