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What modification of the terminal D-alanine residue in peptidoglycan precursors can lead to resistance to certain antibiotics?
What modification of the terminal D-alanine residue in peptidoglycan precursors can lead to resistance to certain antibiotics?
Replacing the terminal D-alanine residue with D-lactate or D-serine
What is the mechanism of action of Bacitracin?
What is the mechanism of action of Bacitracin?
Blocks the dephosphorylation of C55-isoprenyl pyrophosphate and bactoprenol pyrophosphate, preventing the incorporation of peptidoglycan precursors into the cell wall
What is the effect of Bacitracin on gram-positive organisms on the skin?
What is the effect of Bacitracin on gram-positive organisms on the skin?
It is broad spectrum, including gram-positive organisms such as Staphylococcus and Streptococcus
What is the mechanism of action of Polymyxin?
What is the mechanism of action of Polymyxin?
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What is the effect of combining Polymyxin with Gramicidin?
What is the effect of combining Polymyxin with Gramicidin?
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What type of organisms are most susceptible to Polymyxin?
What type of organisms are most susceptible to Polymyxin?
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What is the effect of Bacitracin on kidney function?
What is the effect of Bacitracin on kidney function?
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What is the role of peptidoglycan precursors in bacterial cell wall synthesis?
What is the role of peptidoglycan precursors in bacterial cell wall synthesis?
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What is the primary site of action for aminoglycosides on bacterial ribosomes?
What is the primary site of action for aminoglycosides on bacterial ribosomes?
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What is the consequence of aminoglycosides impairing the proofreading ability of the ribosomal complex?
What is the consequence of aminoglycosides impairing the proofreading ability of the ribosomal complex?
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What is the effect of faulty proteins inserted into the cell membrane due to aminoglycoside action?
What is the effect of faulty proteins inserted into the cell membrane due to aminoglycoside action?
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What is the mode of action of aminoglycosides in terms of bacterial killing?
What is the mode of action of aminoglycosides in terms of bacterial killing?
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Which type of bacteria are aminoglycosides most effective against?
Which type of bacteria are aminoglycosides most effective against?
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What enzymatic activity can confer resistance to aminoglycosides in bacteria?
What enzymatic activity can confer resistance to aminoglycosides in bacteria?
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What type of interaction occurs when trimethoprim and sulfamethoxazole are combined?
What type of interaction occurs when trimethoprim and sulfamethoxazole are combined?
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What type of interaction occurs when antimicrobials and non-antimicrobials are combined, leading to harmful effects?
What type of interaction occurs when antimicrobials and non-antimicrobials are combined, leading to harmful effects?
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Why may antacids negatively impact the absorption of certain antibacterials?
Why may antacids negatively impact the absorption of certain antibacterials?
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What is the effect of antagonistic interactions on drug activity?
What is the effect of antagonistic interactions on drug activity?
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Who discovered the antibacterial action of Penicillium?
Who discovered the antibacterial action of Penicillium?
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What is the name of the journal where Fleming published his discovery?
What is the name of the journal where Fleming published his discovery?
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What is the title of Fleming's publication?
What is the title of Fleming's publication?
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Who wrote about the history of antimicrobial drug discovery?
Who wrote about the history of antimicrobial drug discovery?
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What is the structural difference between cytoplasmic ribosomes in animal cells and those found in bacterial cells?
What is the structural difference between cytoplasmic ribosomes in animal cells and those found in bacterial cells?
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What are the different steps in protein synthesis that can be affected by protein synthesis inhibitors?
What are the different steps in protein synthesis that can be affected by protein synthesis inhibitors?
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What is the characteristic feature of aminoglycosides?
What is the characteristic feature of aminoglycosides?
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Which antibiotic is effective against gram-negative bacteria such as Proteus, Escherichia, Klebsiella, and Serratia?
Which antibiotic is effective against gram-negative bacteria such as Proteus, Escherichia, Klebsiella, and Serratia?
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What is the therapeutic index of protein synthesis inhibitors compared to CW inhibitors?
What is the therapeutic index of protein synthesis inhibitors compared to CW inhibitors?
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What is the name of the textbook that discusses microbial genetics, including protein synthesis?
What is the name of the textbook that discusses microbial genetics, including protein synthesis?
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Which antibiotic is effective against Mycobacterium?
Which antibiotic is effective against Mycobacterium?
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What is the name of the textbook that discusses antimicrobial drugs, including protein synthesis inhibitors?
What is the name of the textbook that discusses antimicrobial drugs, including protein synthesis inhibitors?
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What was used by ancient Egyptians to treat infected wounds?
What was used by ancient Egyptians to treat infected wounds?
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What was used by people in Central Asia to treat infections?
What was used by people in Central Asia to treat infections?
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What was used by the Jewish culture to treat infections?
What was used by the Jewish culture to treat infections?
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What was Paul Ehrlich known as?
What was Paul Ehrlich known as?
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What was the idea developed by Paul Ehrlich?
What was the idea developed by Paul Ehrlich?
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What was the drug developed by Paul Ehrlich for the treatment of syphilis?
What was the drug developed by Paul Ehrlich for the treatment of syphilis?
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What was the result of Paul Ehrlich's work?
What was the result of Paul Ehrlich's work?
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What was the method used by Paul Ehrlich for antimicrobial drug discovery?
What was the method used by Paul Ehrlich for antimicrobial drug discovery?
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Study Notes
Cell Wall Synthesis Inhibitors
- Bacteria like Staphylococcus aureus and Enterococcus have developed resistance to antibiotics by replacing the terminal D-alanine residue with D-lactate or D-serine, altering the drug target.
- Bacitracin is a group of structurally similar peptide antibiotics that block the dephosphorylation of C55-isoprenyl pyrophosphate and bactoprenol pyrophosphate, which are membrane carrier molecules that transport peptidoglycan precursors from the cytoplasm to the cell exterior.
- Bacitracin prevents the incorporation of peptidoglycan precursors into the cell wall, has a broad spectrum, and is effective against gram-positive organisms on the skin, including Staphylococcus and Streptococcus.
- However, Bacitracin has been shown to be nephrotoxic (damaging to the kidneys) and is commonly found in combination with neomycin and polymyxin in topical ointments.
Polymyxin
- Polymyxin is a cyclic polypeptide that inserts into the cell membrane, increasing its permeability and leading to cell death.
- It is most active against gram-negative rods, and is particularly valuable against Pseudomonas aeruginosa and other gram-negative bacilli.
- Polymyxin may be combined with gramicidin, which also increases cell membrane permeability.
Fundamentals
Drug Interactions
- Sometimes, two drugs administered together may provide a synergistic interaction that is better than the efficacy of either drug alone.
- An example of this is trimethoprim and sulfamethoxazole, which are individually bacteriostatic but are bactericidal when combined.
- Antagonistic interactions, on the other hand, can produce harmful effects, such as loss of drug activity, and can occur between two antimicrobials or between antimicrobials and non-antimicrobials being used to treat other conditions.
- The effects of antagonistic interactions can vary depending on the drugs involved, and can cause a range of problems, including decreased absorption of antimicrobials.
Antibiotics
Protein Synthesis Inhibitors
- 80S cytoplasmic ribosomes in animal cells are structurally distinct from those found in bacterial cells (70S), making protein synthesis a good selective target for antibacterial drugs.
- Protein synthesis inhibitors can affect different steps in protein synthesis, including aminoacyl-tRNA binding, peptide bond formation, mRNA reading, and translocation.
- The therapeutic index of protein synthesis inhibitors is fairly high, but not as high as that of cell wall inhibitors.
Ribosome Structure
- Bacterial ribosomes have a 70S structure, consisting of a 50S subunit and a 30S subunit.
- Animal ribosomes have a 80S structure, consisting of a 60S subunit and a 40S subunit.
Aminoglycosides
- Aminoglycosides contain a cyclohexane ring and amino sugars, and are effective against gram-negative bacteria and Mycobacterium.
- Examples of aminoglycosides include streptomycin, gentamycin, kanamycin, neomycin, and tobramycin.
- Aminoglycosides attach irreversibly to the 30S subunit of bacterial ribosomes, blocking the reading of the genetic code on mRNA and inhibiting peptide elongation.
- They are toxic and can cause deafness, renal damage, loss of balance, nausea, and allergic reactions.
- Aminoglycosides impair the proofreading ability of the ribosomal complex, causing mismatches between codons and anticodons, and resulting in the production of proteins with incorrect amino acids.
- These faulty proteins are inserted into the cell membrane, disrupting it and ultimately leading to cell death.
Historical Perspectives
- Antimicrobials have been used for millennia for the treatment of various infections, with examples including ancient Egyptian use of mouldy bread to treat infected wounds, and Central Asian use of mouldy chewed barley and apple paste.
- Paul Ehrlich, known as the father of chemotherapy, discovered the concept of a "magic bullet" and developed Salvarsan, a synthetic chemical that was specific for disease-causing microbes.
- Ehrlich's work established the modern chemotherapeutic era, which involves systematic chemical synthesis with subsequent activity checks.
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Description
Learn about the mechanism of cell wall synthesis inhibitors, such as bacitracin, and how bacteria develop resistance to antibiotics by altering the drug target.
