DNA Gyrase Inhibitor Notes: Downloadable Resources (PDF & PPT)
Download comprehensive notes on DNA gyrase inhibitors in PDF and PPT formats. These notes cover the class of antibiotics known as fluoroquinolones (and their predecessors, the quinolones), which target bacterial DNA gyrase and topoisomerase IV. Learn about their mechanism of action, antibacterial spectrum, clinical uses, resistance mechanisms, and potential side effects. Ideal for students, researchers, and healthcare professionals. Download now for convenient offline access.
Keywords: DNA Gyrase Inhibitor, PDF, PPT, Download, Notes, Antibiotics, Fluoroquinolones, Quinolones, Nalidixic Acid, Ciprofloxacin, Levofloxacin, Moxifloxacin, Ofloxacin, Gemifloxacin, Delafloxacin, Mechanism of Action, Antibacterial, Pharmacology, Topoisomerase, DNA Replication, Bacterial Resistance, Tendonitis, QT Prolongation.
DNA Gyrase Inhibitors: Fluoroquinolones and Their Action
DNA gyrase inhibitors are a class of antibacterial drugs that target bacterial DNA gyrase, an essential enzyme involved in DNA replication, transcription, and repair. The most important and widely used DNA gyrase inhibitors are the fluoroquinolones. This document provides an overview of DNA gyrase inhibitors, with a focus on fluoroquinolones.
DNA Gyrase and Topoisomerase IV: The Targets
DNA gyrase and topoisomerase IV are bacterial type II topoisomerases. Topoisomerases are enzymes that regulate the supercoiling of DNA. During DNA replication and transcription, the DNA double helix must be unwound, which creates torsional stress. Topoisomerases relieve this stress by introducing transient breaks in the DNA strands.
- DNA Gyrase: A bacterial enzyme that introduces *negative* supercoils into DNA. This is essential for compacting the bacterial chromosome and for facilitating DNA replication and transcription. It is a tetramer consisting of two GyrA and two GyrB subunits.
- Topoisomerase IV: Primarily responsible for *decatenation* (separating) newly replicated DNA daughter strands. It is also a tetramer, consisting of two ParC and two ParE subunits.
Mammalian cells have type II topoisomerases, but they are structurally different from the bacterial enzymes, making DNA gyrase and topoisomerase IV excellent targets for selective antibacterial action.
Mechanism of Action of Fluoroquinolones
Fluoroquinolones inhibit bacterial DNA gyrase and topoisomerase IV by binding to the enzyme-DNA complex. This binding:
- Stabilizes the Cleavable Complex: Fluoroquinolones trap the enzyme-DNA complex in a state where the DNA strands are broken but not yet resealed. This is called the "cleavable complex."
- Blocks DNA Replication and Transcription: The presence of these stabilized cleavable complexes blocks the progression of DNA replication and transcription machinery, leading to inhibition of bacterial growth.
- Generates Double-Strand Breaks: The accumulation of cleavable complexes can lead to the formation of double-strand breaks in the bacterial DNA, which can be lethal to the bacteria. Fluoroquinolones are generally considered bactericidal (kill bacteria).
The relative affinity of fluoroquinolones for DNA gyrase versus topoisomerase IV varies depending on the specific drug and the bacterial species. In Gram-negative bacteria, DNA gyrase is often the primary target, while in Gram-positive bacteria, topoisomerase IV is often the primary target.
Classification of Quinolones/Fluoroquinolones
Quinolones are classified into generations based on their antibacterial spectrum and pharmacokinetic properties:
- First-Generation Quinolones:
- Examples: Nalidixic acid, Cinoxacin.
- Spectrum: Narrow spectrum, primarily active against Gram-negative bacteria, particularly those causing urinary tract infections.
- Limitations: Low potency, rapid development of resistance.
- Second-Generation Fluoroquinolones:
- Examples: Ciprofloxacin, Ofloxacin, Norfloxacin.
- Spectrum: Expanded spectrum, including better activity against Gram-negative bacteria (including *Pseudomonas aeruginosa*) and some activity against atypical bacteria (e.g., *Chlamydia*, *Mycoplasma*).
- Improved Pharmacokinetics: Better absorption and tissue penetration compared to first-generation quinolones.
- Third-Generation Fluoroquinolones:
- Examples: Levofloxacin, Moxifloxacin, Gemifloxacin.
- Spectrum: Further expanded spectrum, with improved activity against Gram-positive bacteria (including *Streptococcus pneumoniae*) and atypical bacteria, while maintaining good Gram-negative coverage. Often referred to as "respiratory fluoroquinolones" due to their activity against common respiratory pathogens.
- Fourth-Generation Fluoroquinolones:
- Examples: Delafloxacin
- Spectrum: Broadest spectrum with activity against some MRSA.
Clinical Uses of Fluoroquinolones
Fluoroquinolones are used to treat a variety of bacterial infections, including:
- Urinary tract infections
- Respiratory tract infections (e.g., pneumonia, bronchitis)
- Gastrointestinal infections (e.g., traveler's diarrhea)
- Skin and soft tissue infections
- Bone and joint infections
- Sexually transmitted infections (e.g., gonorrhea - *although resistance is a growing concern*)
- Intra-abdominal infections
*Note: Due to concerns about resistance and potential serious side effects, fluoroquinolones are generally not considered first-line treatment for uncomplicated infections. They are often reserved for more serious infections or when other antibiotics are not effective or cannot be used.*
Bacterial Resistance to Fluoroquinolones
Bacteria can develop resistance to fluoroquinolones through several mechanisms:
- Mutations in Gyrase and Topoisomerase IV Genes: The most common mechanism. Mutations in the genes encoding DNA gyrase (gyrA and gyrB) and topoisomerase IV (parC and parE) can lead to amino acid changes in the enzymes that reduce their affinity for fluoroquinolones.
- Efflux Pumps: Some bacteria have efflux pumps that actively pump fluoroquinolones out of the cell, reducing their intracellular concentration.
- Plasmid-Mediated Quinolone Resistance (PMQR): Plasmids (small, circular DNA molecules) can carry genes that confer resistance to fluoroquinolones. These genes can encode:
- Qnr proteins, which protect DNA gyrase and topoisomerase IV from fluoroquinolone binding.
- Aminoglycoside acetyltransferase (AAC(6')-Ib-cr), an enzyme which can modify certain fluroquinolones.
Side Effects of Fluoroquinolones
Fluoroquinolones are generally well-tolerated, but they can cause a range of side effects, some of which can be serious:
- Gastrointestinal: Nausea, vomiting, diarrhea, abdominal pain.
- Central Nervous System (CNS): Headache, dizziness, insomnia, confusion, seizures (rare).
- Tendonitis and Tendon Rupture: Fluoroquinolones can damage tendons, particularly the Achilles tendon. This risk is increased in older adults, patients taking corticosteroids, and those with a history of tendon problems.
- QT Prolongation: Some fluoroquinolones can prolong the QT interval on an electrocardiogram (ECG), increasing the risk of a potentially fatal heart rhythm (torsades de pointes).
- Phototoxicity: Increased sensitivity to sunlight.
- Peripheral Neuropathy: Nerve damage, which can be permanent.
- Aortic Aneurysm and Dissection: An association, needs more research.
- Clostridioides difficile Infection (CDI): Like other broad-spectrum antibiotics, fluoroquinolones can disrupt the normal gut flora, increasing the risk of CDI.
- Musculoskeletal: Arthralgia.
*The FDA has issued warnings about the potential for serious and disabling side effects associated with fluoroquinolones, and recommends that they be reserved for use in patients who have no other treatment options for certain infections.*
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