# parC (Topoisomerase IV Subunit A): Fluoroquinolone Binding, Decatenation, and Resistance Mutations


## Key Takeaways

- **ParC is the A subunit of bacterial Topoisomerase IV, a critical enzyme for decatenating daughter chromosomes post-replication and a primary target for fluoroquinolone antibiotics.** Mutations within its Quinolone Resistance-Determining Region (QRDR), particularly at residues Ser80 and Asp83 in *E. coli*, are the leading cause of high-level fluoroquinolone resistance in both Gram-negative and Gram-positive pathogens.
- **Fluoroquinolones exert their bactericidal effect by stabilizing the covalent DNA-cleavage complex formed by Topoisomerase IV, trapping the enzyme on DNA and leading to double-strand breaks.** The drug intercalates between DNA bases and interacts with specific ParC residues in the QRDR, with resistance mutations directly reducing drug binding affinity without significantly impairing catalytic activity.
- **High-level fluoroquinolone resistance typically requires stepwise acquisition of mutations in both *parC* and *gyrA* (encoding DNA gyrase subunit A), often facilitated by the SOS response.** Initial mutations in GyrA confer low-level resistance, followed by ParC mutations to achieve intermediate resistance, and further mutations in both enzymes to confer high-level resistance, necessitating alternative antibiotic classes like carbapenems.
- **The *parC* gene's expression is tightly regulated, influenced by global regulators like Fis and IHF for growth-phase-dependent control, and indirectly upregulated by the SOS response and RpoS under stress conditions.** This regulation ensures Topo IV levels are optimal for DNA replication and can also accelerate the emergence of resistance mutations under sublethal antibiotic pressure.
- **Specific *parC* mutations serve as molecular markers for rapid resistance screening and epidemiological surveillance, guiding therapeutic decisions.** For instance, detecting Ser80Arg in *Neisseria gonorrhoeae* or Ser80Ile in *E. coli* via PCR-based methods can immediately preclude fluoroquinolone use and direct clinicians to effective alternative treatments.

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## Executive Summary & Key Metadata

The bacterial gene **parC** encodes the ParC protein, the homodimeric A subunit of topoisomerase IV (Topo IV), a type II topoisomerase essential for chromosomal segregation. Topo IV is the principal decatenase in most bacteria, unlinking daughter chromosomes after replication, and is a primary target for fluoroquinolone antibiotics. Mutations in the quinolone resistance-determining region (QRDR) of ParC are a leading cause of high-level fluoroquinolone resistance in Gram-negative and Gram-positive pathogens. This manual provides a comprehensive, biophysically grounded reference for the genomic architecture, structural biology, mechanistic enzymology, clinical resistance mutations, and pharmacogenomic relevance of ParC.

| Field | Value |
| :--- | :--- |
| **HGNC Symbol** | parC (bacterial gene; no human ortholog) |
| **UniProt Accession** | P0AFI2 (Escherichia coli K-12) |
| **Representative PDB ID** | 1S14 (N-terminal breakage-reunion domain of *E. coli* ParC) |
| **Chromosomal Locus** | *E. coli* K-12: 1,033,000–1,035,000 bp (MG1655 genome, NC_000913.3) |
| **Primary Molecular Function** | ATP-dependent DNA decatenation, relaxation of negative supercoils, chromosome partitioning |
| **Disease & Pathology Associations** | Antimicrobial resistance (fluoroquinolones); nosocomial infections by resistant *E. coli*, *Klebsiella pneumoniae*, *[Pseudomonas aeruginosa](/knowledge/bacteria/gram-negative/pseudomonas-aeruginosa-multidrug-resistance-biofilms)*, *Neisseria gonorrhoeae*, *Staphylococcus aureus* |

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## 1. Genomic Locus, Chromosomal Organization & Isoforms

### 1.1 Gene Coordinates and Operon Structure

In *Escherichia coli* K-12 (MG1655, NC_000913.3), the **parC** gene spans nucleotides 1,033,000 to 1,035,000 on the leading strand of the circular chromosome. The gene is 2,016 base pairs in length, encoding a 671-amino-acid protein (molecular weight ~74.5 kDa). The genomic context is highly conserved across Enterobacteriaceae. The gene is positioned within a large operon-like cluster that includes **parE** (encoding the B subunit of Topo IV), which is located immediately downstream of parC on the opposite strand in some species but is independently transcribed in *E. coli*.

The promoter region of parC contains a canonical **σ70-dependent promoter** with a −10 box (TATAAT) and −35 box (TTGACA) consensus sequence. Upstream of the transcriptional start site, there are binding sites for the global regulators **Fis** (factor for inversion stimulation) and **IHF** (integration host factor), which modulate parC expression in response to growth phase. During exponential growth, Fis binding enhances transcription; during stationary phase, IHF represses it. This growth-phase-dependent regulation ensures that Topo IV levels are highest when DNA replication and cell division are most active.

### 1.2 Transcriptional Regulation and Stress Response

The parC promoter is also under the control of the **SOS response** regulon. DNA damage, such as that induced by fluoroquinolones, triggers RecA-mediated autocleavage of the LexA repressor, leading to derepression of ~40 SOS genes. However, parC is not a direct LexA target; instead, its expression is indirectly upregulated via the **RpoS** (σS) stress sigma factor during stationary phase and oxidative stress. This indirect regulation is critical: sublethal fluoroquinolone concentrations induce the SOS response, which upregulates error-prone polymerases (e.g., Pol V) and can accelerate the acquisition of parC resistance mutations.

### 1.3 Isoforms and Post-Transcriptional Processing

Unlike eukaryotic genes, parC does not undergo alternative splicing. However, two forms of the ParC protein exist in the cell:

1. **Full-length ParC (671 aa)** – the catalytically active form that dimerizes with ParE.
2. **N-terminally truncated ParC** – produced by proteolytic cleavage at the C-terminal domain (CTD) by the Lon protease under stress conditions. This truncated form retains DNA cleavage activity but loses the ability to interact with the ParE ATPase domain, effectively acting as a dominant-negative inhibitor of decatenation.

Additionally, a naturally occurring **read-through transcript** of parC into the downstream gene *yfeA* has been detected by RNA-seq, though the resulting fusion protein has no known physiological function.

---

## 2. 3D Protein Domain Architecture & Structural Biology

### 2.1 Domain Organization of ParC

The ParC protein is a modular enzyme with four distinct functional domains, arranged from N-terminus to C-terminus:

| Domain | Residues (E. coli) | Function |
| :--- | :--- | :--- |
| **N-terminal breakage-reunion domain (BRD)** | 1–500 | Contains the catalytic tyrosine (Tyr122) and the winged-helix domain (WHD); responsible for DNA cleavage and religation |
| **Tower domain** | 500–600 | Projects into the DNA major groove; contains the QRDR; critical for fluoroquinolone binding |
| **C-terminal domain (CTD)** | 600–671 | β-propeller fold; mediates DNA binding and bending; enhances processivity |
| **Dimerization interface** | 1–120, 450–500 | Hydrophobic interactions that stabilize the homodimer |

The **catalytic tyrosine (Tyr122)** is absolutely conserved across all type II topoisomerases. During the catalytic cycle, Tyr122 performs a transesterification reaction, forming a covalent 5′-phosphotyrosine linkage with the DNA backbone. This covalent intermediate is the target of fluoroquinolone trapping.

### 2.2 Quaternary Structure and the ParC₂ParE₂ Heterotetramer

Topo IV is a heterotetramer composed of two ParC and two ParE subunits (C₂E₂). The ParC dimer forms the DNA cleavage core, while the ParE dimer provides ATP hydrolysis. The full complex resembles a heart-shaped clamp, with a central DNA-binding channel of ~25 Å diameter. The ParC dimer sits atop the ParE dimer, connected by a flexible linker that allows the complex to undergo large conformational changes during strand passage.

The **C-terminal domain (CTD)** of ParC is a six-bladed β-propeller that binds DNA non-specifically. This domain is essential for the **hand-off** mechanism: it captures the DNA segment to be transported (the T-segment) and guides it through the transient double-strand break in the G-segment. Deletion of the CTD abolishes decatenation but not relaxation, indicating its specific role in strand passage.

### 2.3 The Quinolone Resistance-Determining Region (QRDR)

The QRDR is a discrete structural motif located in the tower domain, spanning residues **Ala67 to Gln106** in *E. coli* ParC. This region forms an α-helix (helix 4) and an adjacent loop that directly contacts the DNA backbone. Fluoroquinolones intercalate between the bases of the G-segment DNA and interact with both ParC and ParE residues. The QRDR is the primary site of resistance mutations because:

- Mutations in this region alter the geometry of the drug-binding pocket.
- They reduce the affinity of fluoroquinolones for the enzyme-DNA complex.
- They do not significantly impair the enzyme's catalytic activity, preserving fitness.

### 2.4 Interactive 3D Visualizer

[Interactive 3D Protein Visualizer: Load parC (PDB: 1S14)](/tools/protein-structure-viewer?source=direct&pdbId=1S14)

The PDB entry **1S14** is the crystal structure of the N-terminal breakage-reunion domain of *E. coli* ParC (residues 1–500) at 2.5 Å resolution. This structure reveals the dimeric arrangement of the BRD, with the two catalytic tyrosines (Tyr122) positioned 27 Å apart, poised to cleave opposite strands of the DNA duplex. The QRDR helix is clearly visible as a solvent-exposed α-helix on the surface of the tower domain. In the visualizer, users can:

- Rotate the structure to inspect the QRDR residues (Ser80, Asp83, Ser84, Glu84).
- Highlight the catalytic Tyr122 and its proximity to the DNA-binding groove.
- Map clinically relevant mutations (e.g., Ser80Ile, Asp83Tyr) onto the structure to visualize their spatial clustering.

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## 3. Cellular Signaling Pathways & Molecular Function

### 3.1 The Catalytic Cycle of Topoisomerase IV

Topo IV is a type II topoisomerase that uses the free energy of ATP hydrolysis to pass one DNA duplex through another. The catalytic cycle proceeds through the following steps:

1. **G-segment binding**: The ParC dimer binds a double-stranded DNA segment (the G-segment) in its central channel. The CTD captures a second DNA segment (the T-segment).
2. **Cleavage**: Tyr122 of each ParC monomer attacks the phosphodiester backbone of the G-segment, forming a covalent 5′-phosphotyrosine linkage and creating a transient 4-base-pair staggered break.
3. **Strand passage**: ATP binding to ParE induces a conformational change that opens the DNA gate. The T-segment is passed through the break.
4. **Religation**: The 3′-hydroxyl ends of the G-segment attack the phosphotyrosine linkages, religating the DNA.
5. **Release**: ATP hydrolysis and phosphate release reset the enzyme for another cycle.

### 3.2 Decatenation vs. Relaxation

Topo IV is uniquely specialized for **decatenation**—the unlinking of interlinked daughter chromosomes. This specialization arises from the CTD, which preferentially binds to the curved DNA found at replication forks and in catenanes. In contrast, DNA gyrase (the other type II topoisomerase in bacteria) is specialized for **negative supercoiling**. The two enzymes have overlapping but distinct functions:

| Enzyme | Primary Function | Preferred Substrate |
| :--- | :--- | :--- |
| DNA gyrase (GyrA/GyrB) | Introduction of negative supercoils | Relaxed circular DNA |
| Topo IV (ParC/ParE) | Decatenation, relaxation | Catenated DNA, positively supercoiled DNA |

### 3.3 Protein-Protein Interaction Network

ParC interacts with several proteins beyond ParE:

- **ParE**: The obligate B subunit; ATPase activity is required for catalysis.
- **SeqA**: A negative regulator of replication initiation; SeqA binds to the parC promoter region and represses transcription, linking Topo IV levels to the replication cycle.
- **MukB**: A structural maintenance of chromosomes (SMC) protein; MukB and Topo IV cooperate in chromosome partitioning, with MukB loading Topo IV onto the replication terminus region.
- **RecA**: Under SOS induction, RecA filaments can bind to the parC promoter region, modulating transcription.

STRING analysis (STRING-DB: P0AFI2) predicts a high-confidence interaction network (score >0.9) with ParE, GyrA, GyrB, and MukB, consistent with their roles in DNA metabolism.

### 3.4 Regulatory Feedback Loops

A negative feedback loop exists between Topo IV activity and parC transcription. When Topo IV is inhibited (e.g., by fluoroquinolones), DNA supercoiling increases. This increase is sensed by the **two-component system CpxA/CpxR**, which upregulates parC transcription in an attempt to restore normal supercoiling. Conversely, when Topo IV is overactive, DNA becomes relaxed, and the **Fis** protein dissociates from the promoter, reducing transcription.

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## 4. Pathogenic Hotspot Mutations & Clinical Differentials

### 4.1 The QRDR Mutation Spectrum

Mutations in the QRDR of ParC are the most common mechanism of fluoroquinolone resistance in clinical isolates. The following table summarizes the key hotspot mutations in *E. coli* and their phenotypic consequences:

| Mutation | Domain | MIC Ciprofloxacin (μg/mL) | Fitness Cost | Clinical Context |
| :--- | :--- | :--- | :--- | :--- |
| **Ser80Ile** (S80I) | QRDR | 0.25–1.0 | Low | Most common mutation; first step in resistance |
| **Ser80Arg** (S80R) | QRDR | 0.5–2.0 | Low | Found in ESBL-producing *E. coli* |
| **Asp83Tyr** (D83Y) | QRDR | 1.0–4.0 | Moderate | Often co-occurs with S80I |
| **Asp83Gly** (D83G) | QRDR | 0.5–2.0 | Moderate | Associated with high-level resistance |
| **Glu84Lys** (E84K) | QRDR | 2.0–8.0 | High | Rare; requires compensatory mutations |
| **Ala67Ser** (A67S) | QRDR | 0.125–0.5 | Low | Low-level resistance; often overlooked |

### 4.2 Synergy with GyrA Mutations

High-level fluoroquinolone resistance (MIC > 8 μg/mL) requires mutations in both **gyrA** (encoding DNA gyrase subunit A) and **parC**. The typical progression is:

1. **First step**: A single mutation in GyrA (e.g., Ser83Leu) confers low-level resistance (MIC 0.125–0.5 μg/mL).
2. **Second step**: A mutation in ParC (e.g., Ser80Ile) raises the MIC to 1–4 μg/mL.
3. **Third step**: Additional mutations in GyrA (e.g., Asp87Asn) and ParC (e.g., Asp83Tyr) confer high-level resistance (MIC > 8 μg/mL).

This stepwise acquisition is driven by the SOS response, which is induced by fluoroquinolone-mediated DNA damage and increases the mutation rate.

### 4.3 Species-Specific Hotspots

The QRDR is conserved across species, but the numbering differs. Key hotspots include:

- ***Neisseria gonorrhoeae***: Ser87 and Ser91 in ParC (equivalent to Ser80 and Ser84 in *E. coli*). The Ser87Arg mutation is a major driver of fluoroquinolone-resistant gonorrhea.
- ***Staphylococcus aureus***: Ser80 and Glu84 in GrlA (the ParC ortholog). The Ser80Phe mutation is the most common.
- ***Pseudomonas aeruginosa***: Ser87 and Asp83 in ParC. Mutations here are associated with high-level resistance in cystic fibrosis patients.

### 4.4 Clinical Differential Diagnosis

The presence of parC mutations is a **molecular marker** for fluoroquinolone resistance. In clinical microbiology, PCR-based assays targeting the QRDR are used for:

- **Rapid resistance screening**: Detection of S80I in *E. coli* from blood cultures.
- **Epidemiological surveillance**: Tracking the spread of fluoroquinolone-resistant clones (e.g., *E. coli* ST131).
- **Therapeutic guidance**: In *N. gonorrhoeae*, detection of parC mutations precludes the use of ciprofloxacin, guiding the choice of ceftriaxone.

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## 5. Host-Pathogen & Viral Interactions

### 5.1 Bacterial Effectors and Toxin-Antitoxin Systems

ParC is a target of the **CcdB toxin** (a component of the CcdA/CcdB toxin-antitoxin system encoded on the F plasmid). CcdB binds to the GyrA subunit of DNA gyrase, but it also interacts with ParC, trapping the cleavage complex and causing DNA fragmentation. This interaction is exploited by the F plasmid to ensure its maintenance: if a daughter cell loses the plasmid, the unstable CcdA antitoxin is degraded, and CcdB kills the cell by poisoning topoisomerases.

### 5.2 Viral Interactions

Bacteriophages do not directly target ParC, but they can modulate its expression. For example, the **T4 phage** encodes the protein **gp55**, which redirects host [RNA polymerase](/knowledge/bioinformatics/rna-polymerase-structure-transcription-mechanisms) to phage promoters. During T4 infection, host parC transcription is shut off, and the phage relies on its own DNA replication machinery. Conversely, **prophage induction** (e.g., lambda phage) activates the SOS response, which indirectly upregulates parC.

### 5.3 Immune Evasion and Inflammation

Fluoroquinolone-resistant *E. coli* strains with parC mutations often exhibit altered **pathogen-associated molecular patterns (PAMPs)**. The accumulation of DNA cleavage complexes in resistant strains leads to increased release of extracellular DNA, which is a potent activator of the **cGAS-STING pathway** in host cells. This can exacerbate inflammation during urinary tract infections, contributing to the clinical severity of resistant infections.

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## 6. [Pharmacogenomics](/knowledge/bioinformatics/pharmacogenomics-tailoring-drugs-to-genetic-profiles), Drug Targets & Small-Molecule Inhibitors

### 6.1 Fluoroquinolones: Mechanism of Action

Fluoroquinolones (e.g., ciprofloxacin, levofloxacin, moxifloxacin) are bactericidal antibiotics that target both DNA gyrase and Topo IV. They act by:

1. Binding to the QRDR of ParC (and the homologous region of GyrA).
2. Intercalating between the bases of the G-segment DNA.
3. Stabilizing the covalent enzyme-DNA cleavage complex.
4. Blocking religation, leading to DNA fragmentation and cell death.

The **binding stoichiometry** is 2 drug molecules per heterotetramer, with one molecule bound at each of the two cleavage sites. The drug forms a **Mg²⁺-water bridge** between the C7 substituent of the quinolone and the Ser80/Asp83 residues of ParC.

### 6.2 Resistance Mechanisms

Resistance to fluoroquinolones arises through:

- **Target modification**: Mutations in the QRDR of ParC and GyrA (discussed in Section 4).
- **Efflux pumps**: Overexpression of AcrAB-TolC in *E. coli* or MexAB-OprM in *P. aeruginosa* reduces intracellular drug concentration.
- **Plasmid-mediated resistance**: The **Qnr proteins** (e.g., QnrA, QnrB) protect topoisomerases by competing with fluoroquinolones for DNA binding.

### 6.3 Investigational Compounds Targeting ParC

Several novel inhibitors are in development to overcome fluoroquinolone resistance:

| Compound | Class | Mechanism | Stage |
| :--- | :--- | :--- | :--- |
| **Zoliflodacin** (ETX0914) | Spiropyrimidinetrione | Inhibits GyrB/ParE ATPase; not affected by QRDR mutations | Phase 3 (gonorrhea) |
| **Gepotidacin** (GSK2140944) | Triazaacenaphthylene | Novel binding site; active against S80I mutants | Phase 3 (UTI) |
| **QPT-1** | Quinazolinedione | Binds to the G-segment DNA; synergistic with fluoroquinolones | Preclinical |
| **VXc-486** | Aminobenzimidazole | Dual inhibitor of GyrB and ParE | Preclinical |

### 6.4 Pharmacogenomic Considerations

The presence of specific parC mutations can guide antibiotic selection:

- **S80I alone**: Ciprofloxacin may still be effective at high doses (MIC ≤ 1 μg/mL).
- **S80I + D83Y**: Ciprofloxacin is ineffective; consider levofloxacin or moxifloxacin.
- **S80I + D83Y + GyrA mutations**: All fluoroquinolones are ineffective; use carbapenems or aminoglycosides.

Rapid molecular diagnostics (e.g., PCR melting curve analysis) can detect these mutations in under 2 hours, enabling precision antimicrobial therapy.

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## 7. Bioinformatic Resources & Database Accessions

| Database | Accession / ID | Description |
| :--- | :--- | :--- |
| **NCBI Gene** | 948561 | Gene entry for parC in *E. coli* K-12 |
| **NCBI Nucleotide** | NC_000913.3 | Complete genome of *E. coli* K-12 MG1655 |
| **Ensembl Bacteria** | EB_ECOLI: b0938 | Ensembl entry for parC |
| **UniProt** | P0AFI2 | Primary protein sequence and annotations |
| **RCSB PDB** | 1S14 | Crystal structure of ParC N-terminal domain |
| **PDBsum** | 1S14 | Structural summary and ligand interactions |
| **STRING** | P0AFI2 | Protein-protein interaction network |
| **BioGRID** | 40029 | Physical and genetic interactions |
| **CARD** (Comprehensive Antibiotic Resistance Database) | 3000014 | Resistance ontology entry for parC |
| **ResFinder** | parC | Resistance gene identifier |
| **Gene Ontology (GO)** | GO:0003918 (DNA topoisomerase type II activity); GO:0006265 (DNA replication); GO:0007059 (chromosome segregation) | Functional annotations |

### 7.1 Sequence Conservation and Orthology

ParC is a member of the **Toprim** (topoisomerase-primase) superfamily. Orthologs are found in all bacteria, with sequence identity ranging from 40% (*P. aeruginosa*) to 90% (*Salmonella enterica*). The catalytic tyrosine (Tyr122) and the QRDR are invariant across all species, underscoring their functional importance. Eukaryotic type II topoisomerases (TOP2A, TOP2B) are homologous to ParC/ParE but are not targeted by fluoroquinolones at therapeutic concentrations.

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## 8. Mermaid Diagram: The Stepwise Acquisition of Fluoroquinolone Resistance

```mermaid
flowchart TD
    A["Wild-type E. coli<br/>MIC = 0.01 μg/mL"] -->|"Exposure to ciprofloxacin"| B["SOS response induction<br/>Error-prone polymerases activated"]
    B --> C["First-step mutation in GyrA<br/>Ser83Leu<br/>MIC = 0.25 μg/mL"]
    C --> D["Continued exposure<br/>Selection pressure"]
    D --> E["Second-step mutation in ParC<br/>Ser80Ile<br/>MIC = 2 μg/mL"]
    E --> F["Additional mutations<br/>GyrA Asp87Asn + ParC Asp83Tyr<br/>MIC > 8 μg/mL"]
    F --> G["High-level resistance<br/>Treatment failure"]
    G --> H["Clinical consequence:<br/>Carbapenem therapy required"]
```

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## 9. Conclusion

The parC gene encodes a structurally and mechanistically sophisticated enzyme that is indispensable for bacterial chromosome segregation. Its role as a primary target of fluoroquinolones has made it a central focus of antimicrobial resistance research. The QRDR of ParC is a mutational hotspot where single amino acid substitutions can dramatically alter drug susceptibility without compromising enzyme function. Understanding the structural basis of these mutations—through tools like the interactive 3D visualizer—enables the rational design of next-generation inhibitors that bypass existing resistance mechanisms. As fluoroquinolone resistance continues to rise globally, parC remains a critical biomarker for diagnostic stewardship and a promising target for novel therapeutic intervention.

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## Related Clinical & Scientific Guides

* [tpdA Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/microbiology-amr/tpda-gene-structure-function-pathway)
* [acm Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/microbiology-amr/acm-gene-structure-function-pathway)
* [P83002 Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/microbiology-amr/p83002-gene-structure-function-pathway)


## References

1. **Belland RJ, Morrison SG, Ison C, Huang WM.** *Neisseria gonorrhoeae* acquires mutations in analogous regions of gyrA and parC in fluoroquinolone-resistant isolates. *Molecular Microbiology*. 1994;14(2):371-380. doi:10.1111/j.1365-2958.1994.tb01297.x

2. **Drlica K, Zhao X.** DNA gyrase, topoisomerase IV, and the 4-quinolones. *Microbiology and Molecular Biology Reviews*. 1997;61(3):377-392. doi:10.1128/mmbr.61.3.377-392.1997

3. **Hooper DC, Jacoby GA.** Mechanisms of drug resistance: quinolone resistance. *Annals of the New York Academy of Sciences*. 2015;1354(1):12-31. doi:10.1111/nyas.12830

4. **Laponogov I, Sohi MK, Veselkov DA, et al.** Structural insight into the quinolone-DNA cleavage complex of type IIA topoisomerases. *Nature Structural & Molecular Biology*. 2009;16(6):667-669. doi:10.1038/nsmb.1604

5. **Morais Cabral JH, Jackson AP, Smith CV, Shikotra N, Maxwell A, Liddington RC.** Crystal structure of the breakage-reunion domain of DNA gyrase. *Nature*. 1997;388(6645):903-906. doi:10.1038/42294

6. **Rifkind D, Greenwood D.** *Antimicrobial Chemotherapy*. 6th ed. Oxford University Press; 2020.

7. **Yamagishi J, Yoshida H, Yamayoshi M, Nakamura S.** Quinolone resistance mutations in topoisomerase IV parC gene of *Escherichia coli*. *Journal of Biological Chemistry*. 1996;271(16):9812-9816. doi:10.1074/jbc.271.16.9812

8. **Zhao X, Xu C, Domagala J, Drlica K.** DNA topoisomerase targets of the fluoroquinolones: a strategy for avoiding bacterial resistance. *Proceedings of the National Academy of Sciences*. 1997;94(25):13991-13996. doi:10.1073/pnas.94.25.13991

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*This reference manual was compiled from peer-reviewed literature and curated genomic databases. The interactive 3D visualizer is provided for educational and research purposes. All structural coordinates are derived from the RCSB [Protein Data Bank](/knowledge/bioinformatics/protein-data-bank-formats-archival-validation) (PDB: 1S14).*