ß-Lactams: Mechanisms of Action and Resistance
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- เผยแพร่เมื่อ 9 พ.ค. 2024
- Developed and produced by www.MechanismsinMedicine.com
Animation Description: This animation starts with the explanation of bacterial cell wall synthesis, the process targeted by ß-Lactams.
Structurally, most bacteria consist of a cell membrane surrounded by a cell wall and, for some bacteria, an additional outer layer. Internal to the cell membrane is the cytoplasm which contains ribosomes, a nuclear region and in some cases granules and/or vesicles. Depending on the bacterial species, a number of different external structures may be found such as a capsule, flagella and pili.
In gram negative bacteria, the gap between the cell membrane and the cell wall is known as the periplasmic space. Most gram positive bacteria do not possess a periplasmic space but have only periplasm where metabolic digestion occurs and new cell peptidoglycan is attached. Peptidoglycan, the most important component of the cell wall, is a polymer made of N-acetyl muramic acid alternating with N-acetyl glucosamine which are cross-linked by chains of four amino acids. The function of the bacterial cell wall is to maintain the characteristic shape of the organism and to prevent the bacterium from bursting when fluid flows into the organism by osmosis.
Synthesis of peptidoglycan and ultimately the bacterial cell wall occurs in a number of stages. One of the first stages is the addition of 5 amino acids to N-acetyl muramic acid. Next, N-acetyl glucosamine is added to the N-acetyl muramic acid to form a precursor of peptidoglycan. This peptidoglycan precursor is then transported across the cell membrane to a cell wall acceptor in the periplasm.
Once in the periplasm, the peptidoglycan precursors bind to cell wall acceptors, and undergo extensive crosslinking. Two major enzymes are involved in crosslinking: transpeptidase and D-alanyl carboxypeptidase. These enzymes are also known as penicillin binding proteins because of their ability to bind penicillins and cephalosporins.
Eventually, several layers of peptidoglycan are formed all of which are crosslinked to create the cell wall. Gram positive bacteria have many more layers than gram negative bacteria and thus have a much thicker cell wall.
Beta-lactam antibiotics include all penicillins and cephalosporins that contain a chemical structure called a beta-lactam ring. This structure is capable of binding to the enzymes that cross-link peptidoglycans.
Beta-lactams interfere with cross-linking by binding to transpeptidase and D-alanyl carboxypeptidase enzymes, thus preventing bacterial cell wall synthesis.
By inhibiting cell wall synthesis, the bacterial cell is damaged. Gram positive bacteria have a high internal osmotic pressure. Without a normal, rigid cell wall, these cells burst when subjected to the low osmotic pressure of their surrounding environment. As well, the antibiotic-penicillin binding protein complex stimulates the release of autolysins that are capable of digesting the existing cell wall. Beta-lactam antibiotics are therefore considered bactericidal agents.
Bacterial resistance to beta-lactam antibiotics may be acquired by several routes. One of the most important mechanisms is through a process known as transformation. During transformation, chromosomal genes are transferred from one bacterium to another.
When a bacterium containing a resistance gene dies, naked DNA is released into the surrounding environment. If a bacterium of sufficient similarity to the dead one is in the vicinity, it will be able to uptake the naked DNA containing the resistance gene.
Once inside the bacterium, the resistance gene may be transferred from the naked DNA to the chromosome of the host bacteria by a process known as homologous transformation. Over time, the bacterium may acquire enough of these resistance genes to result in a remodelling of the segment of the host DNA.
If this remodelled DNA segment codes for cross-linking enzymes (i.e. penicillin binding proteins), the result is the production of altered penicillin binding proteins.
These altered penicillin binding proteins can still cross-link the peptidoglycan layers of the cell wall but have a reduced affinity for beta-lactam antibiotics thus rendering the bacterium resistant to the effects of penicillin and other beta-lactam agents. This transfer process has resulted in penicillin-resistant S. pneumoniae through the acquisition of genes from other naturally occurring penicillin-resistant Streptococcus species.
A second important mechanism by which bacteria become resistant to beta-lactam antibiotics is by the production of enzymes capable of inactivating or modifying the drug before it has a chance to exert its effect on the bacteria.
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there's no systematic evidence to suggest anyone is any more a verbal than a visual learner. you're probably trying to say that this was a good video. i agree.
Thank you for your comment. At times it's beneficial to omit certain details for the sake of clarity of overall picture.
Thank you! New videos will be uploaded in coming days. Please stay tuned.
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Surprisingly, the video gave a simple, yet relevant and helpful explanation to a very complicated MOA.
The best visual understanding of Pharmacology Mechanism of Action and Resistance
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Thank you for the video. I have been reading about penicillin and cephalosporin antibiotics and having a visual aid has helped immensely.
Wow! This is amazing. Thanks a million
At this time there are no plans for additional animations on inhibitors. You may review other existing videos on our channel that cover antibacterial agents: "Macrolides: Mechanisms of Action and Resistance" and "Fluoroquinolones: Mechanisms of Action and Resistance".
Please note: The animations represent a visual interpretation and are not intended to provide, nor substitute as, medical and/or clinical advice.
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@yaash29
Sincerely thank you for your evaluation! We glad it helps clearly to understand the subject matter.
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No, not at this moment. We may consider your suggested topic for our future animations. Thank you.
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Good explanation. I was hoping for an clarification of the D-ala D-ala structural analogy of vancomycin and penicillin though their mechanism is different.
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excellent video, very strait forward. I was thinking transpeptidase was the pentapeptide chain, most videos do not show the actual enzyme at work. Thank you
Bacterial cell wall synthesis: 0:10 - 3:36Resistant mechanism: 5:19 -7:20
I was learnt this concept after I saw this view..thanku ... then I am requesting one video for cycle of grep cycle...and tca cycle...
fantastic explanation.but im confused about the plasmid donation. as i know the begger bacterium who has not useful plasmid send a strand DNA to copy the wanted plasmid.not as shown here.some on give a comment.thank you
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