Questions and Answers
What is the metabolic pathway of azithromycin in the liver?
Oxidation and hydrolysis of the lactone
Which of the following statements about azithromycin are true? (Select all that apply)
Chloramphenicol is the first broad-spectrum oral antibiotic used in the U.S.
True
What is the limited use of Chloramphenicol attributed to?
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Which infections are treated with Chloramphenicol?
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What is the main action of azithromycin on the macrolide ring?
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Which of the following are types of antibacterials that inhibit protein synthesis?
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What are the two main tRNA binding sites of ribosomes?
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Doxycycline is used for the treatment of peptic ulcer disease caused by Helicobacter pylori infection.
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What is the essential feature for the antimicrobial activity of tetracyclines?
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Tetracyclines are amphoteric substances with three pKa values approximately: ____.
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What causes the insolubility of tetracyclines when chelated with metal ions?
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Which of the following antibiotics is effective against MRSA?
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The presence of the tricarbonyl system of ring A in tetracyclines aids in enolization.
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What is the first aminoglycoside antibiotic that was isolated?
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Match the following antibiotics with their source:
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The average serum half-lives of most tetracycline antibiotics are long, typically between ____ hours.
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What is the primary mechanism of bacterial resistance to aminoglycosides?
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What is Amikacin derived from?
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Tobramycin has a broader spectrum than Kanamycin.
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Which of the following antibiotics is used for the treatment of tuberculosis?
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What is the major constituent of Gentamicin?
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What is one common adverse effect of aminoglycosides?
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Aminoglycosides are effective against anaerobic bacteria.
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The chemical structure of aminoglycosides typically includes a macro cyclic ______.
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What is Clarithromycin?
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Match the following aminoglycosides with their key characteristics:
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Study Notes
Antibacterials That Inhibit Protein Synthesis
- Major classes: Tetracyclines, Aminoglycosides, Macrolides, and Miscellaneous agents.
- Mechanism: Inhibition occurs at ribosomal RNA active sites, affecting protein synthesis.
Tetracycline Overview
- Tetracyclines possess a four-ring structure, effective against Helicobacter pylori in peptic ulcer treatment.
- Doxycycline is used for malaria chemoprophylaxis.
Structure-Activity Relationships (SAR) of Tetracycline
- Southern and eastern faces of the molecule are critical for activity.
- The 4-position dimethylamino function is vital; the α-epimer is more potent than the β-epimer.
- Various functional groups at positions 5, 6, and 8 maintain activity; position 7 allows diverse substitutions.
Common Tetracyclines
- Natural products: Tetracycline, Chlortetracycline, Oxytetracycline, Demethylchlortetracycline.
- Semisynthetic: Minocycline and Doxycycline.
- Tigecycline (Tygacil®): Latest tetracycline, effective against resistant strains including MRSA.
Chemical Properties of Tetracyclines
- Amphoteric with three pKa values (2.8-3.4, 7.2-7.8, 9.1-9.7).
- Administered as water-soluble hydrochloride salts; can form chelates with metal ions, impacting absorption.
Chelation in Tetracyclines
- Tetracyclines can form insoluble salts with divalent and trivalent metals, leading to decreased absorption.
- Implications: Incompatible with antacids, hematinics, and dairy products.
Epimerization and Stability
- Epimerization at the C-4 center can reduce antimicrobial activity.
- Dehydration of tetracyclines leads to biologically inactive products; discoloration indicates degradation.
Base-Catalyzed Cleavage
- Compounds with a C-6-hydroxyl group can cleave in alkaline solutions, generating inactive isotetracyclines.
Mechanism of Action
- All tetracycline rings interact with the ribosome, particularly Ring D, which aids in binding to rRNA.
- Not recommended for empirical treatment due to widespread resistance; accumulated in breast milk and contraindicated in pregnancy.
Bacterial Resistance to Tetracyclines
- Mechanisms include ribosomal protection proteins and energy-dependent efflux, resulting in cross-resistance among tetracyclines.
Aminoglycoside Overview
- Characterized by an aminocyclitol backbone with glycosidically linked aminosugars; broad-spectrum agents against Gram-negative and Gram-positive bacteria.
Aminoglycoside Mechanism and Resistance
- First aminoglycoside, Streptomycin, active against Mycobacterium tuberculosis.
- Resistance often arises from enzymatic inactivation of specific rings.
Specific Aminoglycosides
- Kanamycin: Stable, used against Gram-negative bacteria; modifications can influence activity.
- Amikacin: A semisynthetic derivative of Kanamycin; effective against resistant strains.
- Gentamicin: A mixture from Micromonospora spp., effective against diverse bacterial strains including Pseudomonas.
Clinical Implications
- Aminoglycosides are less toxic due to structural modifications, enhancing stability and efficacy for treating various bacterial infections.### Gentamicins and Modifications
- Gentamicins feature a secondary amino group at 6'-NH2, contributing to spatial hindrance.
- Different types include Gentamicin C1 (R1=R2=CH3), C2 (R1=CH3, R2=H), and C1a (R1=R2=H).
- Gentamicins exhibit varying resistance: AAC-resistant and APH-resistant strains.
- Gentamicin C1a has axial and tertiary 4''-OH compared to the equatorial secondary 4''-OH found in Kanamycin.
Tobramycin
- Tobramycin lacks the C-3′ hydroxyl group, making it resistant to APH(3′)-1 and APH(3′)-II.
- It has a broader antibacterial spectrum than kanamycin and is effective against gentamicin-resistant Pseudomonas aeruginosa.
- Administered parenterally or by inhalation, it is notably less toxic than gentamicin.
Streptomycin
- Introduced primarily to treat tuberculosis; differs from typical aminoglycosides with a modified pharmacophore.
- Contains two guanido groups at C-1 and C-3 instead of primary amines.
- The α-hydroxyaldehyde moiety leads to instability during autoclaving, requiring sterilization by ultra filtration.
- Effective against tuberculosis, plague, and some GIT infections.
Bacterial Resistance Mechanisms
- Bacteria inactivate aminoglycosides using specific enzymes: AAC (N-acetylation), APH (O-phosphorylation), and ANT (O-adenylation).
- Resistance may also result from mutations decreasing binding affinity and reduced drug uptake due to competitive inhibition by Ca2+ and Mg2+ ions.
- Anaerobic bacteria are generally resistant due to lack of ATP-dependent uptake processes.
Aminoglycoside Modifications
- Structural alterations can maintain broad-spectrum activity while evading inactivating enzymes.
- Modifications include removing susceptible functional groups or introducing alternative groups that lessen enzyme interactions.
Therapeutic Use
- Aminoglycosides are primarily reserved for severe Gram-negative infections due to their toxicity.
- Streptomycin is preferred for tuberculosis, while spectinomycin is used for gonorrhea; other aminoglycosides are less effective for these infections.
Adverse Effects
- Ototoxicity affects the 8th cranial nerve, leading to vertigo and irreversible deafness.
- Nephrotoxicity is related to blood levels and impacts kidney cells.
- Rarely, they can cause curare-like neuromuscular blockade, particularly worsening muscle weakness in certain conditions.
Properties of Macrolides
- Common features include a macrolide ring typically containing 12-16 atoms and one or two aminosugars.
- Macrolides are stable at room temperature but unstable under acidic conditions, leading to inactive cyclic ketones.
Key Macrolides
- Erythromycin, discovered in 1952, is chemically unstable and rapidly forms inactive cyclic ketals in acidic conditions.
- Clarithromycin (6-methyl ether of erythromycin) shows improved acid stability and oral bioavailability with reduced gastrointestinal side effects.
- Azithromycin (ring-expanded analogue of erythromycin) has a longer half-life, allowing once-daily dosing and broader antibacterial spectrum.
Chloramphenicol
- First broad-spectrum oral antibiotic in the U.S., effective against typhoid fever, Haemophilus, and rickettsial infections, with limited use due to toxicity.
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Description
Test your knowledge on antibacterials that inhibit protein synthesis, including Tetracycline, Aminoglycosides, Macrolides, and more. This quiz also covers the mechanisms of action of these inhibitors and the role of ribosomes in protein synthesis. Challenge yourself with these critical concepts in microbiology.
