يملعلا قيرفلا –
SCIENTIFIC TEAM 1
يحرلا نمحرلا هللا مسب م
Cell wall inhibitors
The first category of antibiotics that we will discus is cell wall inhibitors
Cell wall inhibitors is not just only very common in clinical medicine ,also many of very effective broad spectrum of antibiotic also
relong to this category of antimicrobial agent . so its very important to know every single detail about cell wall inhibitors
We mentioned that the base for selection toxicity for cell wall inhibitors is that they able to target bacterial cell wall which isn’t existent in mammal human cells , which mean that cell wall
inhibitors can target bacteria without harming normal human cells, because normal human cells don’t have bacterial cell wall
Both gram negative and positive bacteria have a layer of cell wall that out line the cell membrane . cell membrane exist in both eukaryotic and prokaryotic cells ,that response for regulating the permeability of substance . its a thick layer of proteoglycan that maintain the structure integrity . bacterial cell wall is not contribute much to permeability of substance across cell membrane
pharmacology Lecture 28
Date : 26/12/2020
روتكدلا ملاك :دوسلأا
:قرزلأا ديلاسلا
يملعلا قيرفلا –
SCIENTIFIC TEAM 2
In gram positive layer has a single layer or micromolecular layer of cell wall . it’s a thick composed of peptidoglycan (backbone of sugar) .these threads of peptidoglycan connected to each other by peptide molecule
In gram negative bacteria has also a layer of peptidoglycan in addition to an outer layer (outer membrane ) which in structure similar to inner membrane and between them it has a rigid layer (periplasm). In gram negative it has protein channels called porin that facilitate the entry of certain chemical substance to membrane
The cell wall synthesis it self is very complex process that involve several enzymatic pathways ,we have 3 main stages :
1. Cytoplasmic stage :include synthesis of the building blocks or units for the peptidoglycan cell wall within the cytoplasm
2. Cytoplasmic membrane stage :these building units transfer or transport through special membrane receptors into the external peptidoglycan
3. The most important stage (extracellular membrane stage ):
when you want actually form the bacterial cell wall to the exterior of the bacterial cell wall . glycan form the backbone of wall ,then peptides connected to them . in order to make the structure more compound .one of the most important stager of cell wall stages in transpeptidation via PBP. Each peptide molecule connected to glycan backbone cross linkage between peptides (this step is catalyzed by group of enzymes called penicillin binding protein PBP)
يملعلا قيرفلا –
SCIENTIFIC TEAM 3
In the left box, we have several penicillin that are commonly used now days in a clinic . the thing that is common between these family of penicillin is there chemical structure ,basic chemical structure of penicillin : first they have for atom in a ring
composition called lactam ring (3 carbon and 1 nitrogen ) which is connect to the sulfur containing acidic group called
6-aminopenicillinic acid. The difference between these drugs is : The b lactam ring has aside chain alkaline group (R)this can be different ,the R group determine the antimicrobial spectrum ,its also effected the bacterial mechanism certain other pharmacokinetic properties (penetration through membranes to cell wall, etc)
One of the bacterial resistance mechanism to cell wall inhibitors that bacteria able to produce lactamases or penicillinases ,these enzymes have ability to hydrolyze or cleave the b-lactam ring .which mean that can break the drug molecule (target =b-lactam ring )
Penicillin binding proteins are responsible to mediate the third step of bacterial cell wall synthesis.
The PBP are target for cell wall inhibitors .its include variable
different types of bacteria and have different sensitivity to cell wall inhibitors ,its also contribute to bacterial resistance against cell wall inhibitors
Mechanism of action of drugs :
They inhibit cell wall synthesis by directly binding to PBP which are the enzymes that have transpeptidation or cross linkage of the peptide with in peptidoglycan cell wall.
يملعلا قيرفلا –
SCIENTIFIC TEAM 4
The result of this step :
1. Will generate a very weak bacterial cell which mean the fluid will shift toward the inside of the bacteria, then will cause enlargement of the bacteria resulting bacterial killing ,so penicillin bactericidal .
2. Time dependent killing : to maintain the plasma drug
concentration at higher or minimum inhibitory concentration of the drug most of the time of treatment .so penicillin is given more than one dose a day .
3. Penicillin able to destroy cell wall ,they will be required to
bacteria to be rapidly growing ,because bacteria is growing slowly or inhibited and not produce new cell wall, the penicillin will not be effective
According to antimicrobial bacterial spectrum ,we can divide four category :
regarding to chemical structure
1. natural penicillin : the two important drugs: penicillin G, penicillin V both are naturally derived ,penicillin is produce by fungus type .alexander fleming found penicillium chrysogenum . this fungi produce penicillin. When he made a purification for this
substance ,he found that has a bactericidal effect .after many years we expect that penicillin is no longer to using in clinical medicine, because it will have many resistance .but penicillin is still used in treatment of many disease .
drugs of choice for treatment of gas gangrene caused by
(clostridium perfringens ) characterized by soft tissue skin . and drugs of choice for treatment of syphilis caused by treponema pallidum .
يملعلا قيرفلا –
SCIENTIFIC TEAM 5
in fact, patient who have primary or secondary syphilis are usually treated with just single of penicillin G.
penicillin V is different from penicillin G.
penicillin G is given intramuscular ,but penicillin V is given just oral and dosent have a wide clinical using
this slide very important
the second category of antimicrobial spectrum :
2. Extended –spectrum or semisynthetic penicillins : Why we called it like this ?
a. Because it has antimicrobial spectrum wider than natural penicillin b. Because it isn’t completely natural ,they have the same structural
backbone penicillin ,but we make synthetic modification (half in half)
يملعلا قيرفلا –
SCIENTIFIC TEAM 6
Ampicillin, amoxicillin :both drugs have a little wider spectrum than natural penicillin and they include several gram negative rods : E.coli, H.influenzae, etc .
In addition to, several type of enterococci that can cause common infection
Ampicillin :can treatment listeria monocytogenes . and isn’t given orally
Amoxicillin :is a prophylactic antibiotic .because is given orally.
The main resistance mechanism for B-lactamase is that the bacteria has ability of producing enzymes (B-lactamase or
penicillinase ) that can hydrolyze or cleave B-lactam ring of cell wall inhibitors penicillins. So, the most solution was to combined with lactamase inhibitors (chemical substance that can inhibit B-lactamase in bacteria to allow to lactam drugs to work)
If you combined the semisynthetic antibiotic with like amoxicillin and ampicillin with B-lactamase inhibitors ,become effective against methicillin susceptible S.AUREUS (MSSA), because MSSA have the ability to produce many B-lactamases .
The third category :
Antistaphylococcal penicillins : it can target staphylococcus aureus They are : methicillin , nafcillin, oxacillin ,dicloxacillin .
Effective against MSSA they are produce B-lactamase or penicillinase ----(not effective against MRSA )
يملعلا قيرفلا –
SCIENTIFIC TEAM 7
Methicillin not used clinically (just in lap ) because its high toxicity to kidney (nephritis )
The 1st 3 category have a weak limited antimicrobial activity against gram negative bacteria .
The fourth category is :
Antipseudomonal penicillins : have a wide antimicrobial coverage against gram negative rods :
Enterobacter species ,E.coli , proteus mirabilis, p.aeruginosa ,etc.
Such as : piperacillin , which is effected against gram negative and can be combined with lazobactam .
Mechanism of bacterial resistance :
1. Intrinsic resistance : inherenty , they are resistance for penicillin .
Penicillin active in organism have cell wall
Some lack cell wall like microplasm pneumonia , very common pathogen (when target of drug is not exist , the effect of drug will be lost )
2. Acquired resistance :
Mostly resistance are usually mediated through plasmids.
Gram negative and positive are differ in produce B-lactamase .
Gram positive :secrete B-lactamase in the outside , and can target penicillin molecule in the external of the bacterial cell wal.
Gram negative : secreted in the periplasmic B-lactamase between the outer and inner membrane .
يملعلا قيرفلا –
SCIENTIFIC TEAM 8
HOW PROBLEM SOLVED
We are able to design several chemicals called B-lactamase inhibitors .
These drugs are able to combine with bacterial enzymes (B-lactamase )and stop their function
Clavulanic :which is the most common combine with amoxicillin (trade name : amoclan )
Sulbactame : combined with ampicillin
Tazobactam is usually combine with piperacilllin .
B-lactamase inhibitors are help penicillin to extract their function , but these inhibitors don’t have any bacterial function .
To be sure , we have an experiment :in bacterial cell culture you can messure the number of viable bacteria over time . if you look to control condition (no drug in bacteria ), the bacteria can going to grow and divide(their number will increase ). When we put a
clavulanic acid alone also their number will increase (which mean it hasn’t antibacterial effect ). When we put amoxicillin only we observed that it has a very little reduction in cell viability. Because E.coli can secrete many B-lactamase that hydrolyze amoxicillin.
But when u combine amoxicillin with clavulanic acide , they help each other to block the effect of B-lactamase to produce by E.coli without any cleaving.
Certain bacterial types will be able to change permeability outer membrane .in away ,it will prevent further diffusion of cell wall inhibitors to the interior .
يملعلا قيرفلا –
SCIENTIFIC TEAM 9
-klebsiella pneumonia was able to produce efflux pump on the cell membrane . these pumps observed the molecule when inter the membrane, then it pumps outer the membrane
Altered PBP:
Some bacteria are able through genetic mutation to alter or modified the structure of PBP….loss of affinity to bind of B-lactams. Usually happen by MRSA , because MRSA have the ability to alter the structure of PBP
