# gyrA (DNA Gyrase Subunit A): Quinolone Resistance Determining Region (QRDR) and Supercoiling


## Key Takeaways

- The `gyrA` gene encodes the GyrA subunit of bacterial DNA gyrase, a critical type II topoisomerase essential for DNA supercoiling, replication, transcription, and recombination.
- Quinolone and fluoroquinolone antibiotics target the Quinolone Resistance-Determining Region (QRDR) within the GyrA subunit, stabilizing the DNA cleavage complex and leading to cell death.
- Mutations within the QRDR, particularly at residues Ser83 and Asp87 in *E. coli*, are the primary mechanism of clinical resistance to quinolones, reducing drug binding affinity and allowing DNA religation.
- Detection of specific `gyrA` QRDR mutations via PCR-RFLP or DNA sequencing is a standard genotypic method for predicting fluoroquinolone susceptibility in clinical isolates.
- Beyond QRDR mutations, resistance can be modulated by mutations in the GyrB subunit or by extragenic mechanisms such as efflux pumps and plasmid-mediated Qnr proteins.
- Investigational therapies like zoliflodacin and gepotidacin target DNA gyrase through novel mechanisms, aiming to overcome existing quinolone resistance pathways.

---

## Executive Summary & Key Metadata

DNA gyrase is a bacterial type II topoisomerase that catalyzes the ATP-dependent introduction of negative supercoils into DNA. The enzyme is a heterotetramer composed of two GyrA and two GyrB subunits. The `gyrA` gene encodes the GyrA subunit, which contains the active-site tyrosine responsible for the transient double-strand break during the catalytic cycle. GyrA is the primary molecular target of quinolone and fluoroquinolone antibiotics. Mutations within the quinolone resistance-determining region (QRDR) of GyrA reduce drug binding and confer clinical resistance. This manual provides a comprehensive, publication-grade reference on the `gyrA` gene, covering its genomic organization, structural biology, mechanistic function, clinical mutation landscape, and pharmacogenomic relevance.

| **Attribute** | **Value** |
| :--- | :--- |
| **HGNC Symbol** | gyrA (bacterial gene; no human ortholog) |
| **UniProt Accession** | P0AES4 (*Escherichia coli* GyrA) |
| **Representative PDB ID** | 1AB4 (*E. coli* GyrA N-terminal domain, 59 kDa fragment) |
| **Chromosomal Locus** | *E. coli* K-12: 50.3 min (2,338,000–2,340,700 bp) |
| **Primary Molecular Function** | ATP-independent DNA cleavage/rejoining; supercoiling catalysis (with GyrB) |
| **Disease & Pathology Associations** | Antimicrobial resistance (AMR) to quinolones/fluoroquinolones; nosocomial and community-acquired infections |

---

## 1. Genomic Locus, Chromosomal Organization & Isoforms

### 1.1 Gene Coordinates and Context

In *Escherichia coli* K-12, the `gyrA` gene is located at approximately 50.3 minutes on the genetic map, corresponding to base pairs 2,338,000 to 2,340,700 on the circular chromosome (NCBI Reference Sequence: NC_000913.3). The gene is transcribed counterclockwise relative to the origin of replication (`oriC`). The coding sequence spans 2,628 nucleotides, encoding a protein of 875 amino acids with a predicted molecular mass of approximately 97 kDa [1]. The gene is highly conserved across Gram-negative and Gram-positive bacteria, with orthologs identified in *[Pseudomonas aeruginosa](/knowledge/bacteria/gram-negative/pseudomonas-aeruginosa-multidrug-resistance-biofilms)* [2, 3], *Klebsiella pneumoniae* [4, 5], *Campylobacter jejuni* [6], *Streptococcus pneumoniae* [7, 8], *Staphylococcus aureus* [9], and *Mycobacterium tuberculosis* [10, 11].

### 1.2 Promoter Architecture and Transcriptional Regulation

The `gyrA` promoter region contains a canonical −10 (TATAAT) and −35 (TTGACA) consensus sequence recognized by the σ70 subunit of [RNA polymerase](/knowledge/bioinformatics/rna-polymerase-structure-transcription-mechanisms). Upstream of the promoter, a binding site for the nucleoid-associated protein FIS (factor for inversion stimulation) has been identified. FIS binding modulates `gyrA` expression in response to growth phase and supercoiling status. The promoter is also regulated by the global transcriptional regulators CRP (cAMP receptor protein) and IHF (integration host factor), which respond to metabolic and environmental cues.

Supercoiling itself acts as a feedback regulator: when DNA is relaxed, `gyrA` transcription increases; when DNA is hypernegative, transcription decreases. This homeostatic loop is critical for maintaining optimal superhelical density (σ ≈ −0.05) required for replication, transcription, and recombination [12, 13]. The cold shock response in *E. coli* also involves `gyrA`; upon temperature downshift, `gyrA` expression is transiently induced to compensate for reduced gyrase activity at low temperatures [12].

### 1.3 Alternative Splicing and Isoforms

Bacteria lack spliceosomal machinery; however, `gyrA` can produce functionally distinct protein isoforms via alternative translational start sites and post-translational processing. In *Borrelia burgdorferi*, a naturally occurring C-terminal domain of GyrA (Gac) is synthesized as a separate protein from an internal promoter within the `gyrA` coding sequence [14, 15]. This Gac protein retains DNA-binding activity and functions as a chromosome-partitioning factor. In mycobacteria, `gyrA` contains inteins—self-splicing protein elements that are excised post-translationally, yielding a mature GyrA protein. The presence and sequence of these inteins serve as taxonomic markers for mycobacterial species [11, 16].

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

### 2.1 Domain Organization

The GyrA protein is organized into two major functional domains:

1. **N-terminal domain (NTD)** (residues 1–523 in *E. coli*): Contains the catalytic core, including the active-site tyrosine (Tyr122 in *E. coli*), the QRDR, and the DNA cleavage/religation machinery. The NTD is further subdivided into:
   - **Winged-helix domain (WHD)** (residues 1–220): Contains the active-site tyrosine and the QRDR.
   - **Tower domain** (residues 220–330): Forms the DNA-gate and interacts with the GyrB subunit.
   - **Coiled-coil domain** (residues 330–523): Mediates dimerization and DNA wrapping.

2. **C-terminal domain (CTD)** (residues 524–875): A six-bladed β-propeller structure (also known as the "C-terminal β-pinwheel") that binds DNA and is essential for the introduction of negative supercoils. The CTD wraps DNA around the gyrase complex, directing the topology of the supercoiling reaction [14, 15].

### 2.2 Active Site and QRDR

The active-site tyrosine (Tyr122 in *E. coli*; Tyr122 in *P. aeruginosa*; Tyr123 in *S. aureus*) forms a covalent phosphotyrosine linkage with the 5′-phosphate of the DNA backbone during the cleavage reaction. The QRDR spans residues 67–106 in *E. coli* and includes highly conserved amino acids critical for quinolone binding: Ala67, Gly81, Ser83, Ala84, Asp87, and Gln106. Mutations at Ser83 (to Leu, Trp, or Ala) and Asp87 (to Asn, Gly, or Tyr) are the most frequently observed in clinical isolates and confer high-level fluoroquinolone resistance [17, 18, 19, 20, 21, 22].

### 2.3 Quaternary Structure

GyrA dimerizes through its C-terminal domain, forming a heart-shaped dimer. Two GyrB monomers associate with the GyrA dimer to form the active A₂B₂ heterotetramer. The GyrB subunits contain the ATPase domain and interact with the N-terminal domain of GyrA to form the DNA-gate. The full complex binds ~120–150 bp of DNA, wrapping it around the CTD before cleavage and strand passage [1, 23].

### 2.4 Interactive 3D Visualizer

[Interactive 3D Protein Visualizer: Load gyrA (PDB: 1AB4)](/tools/protein-structure-viewer?source=direct&pdbId=1AB4)

The PDB entry 1AB4 corresponds to the 59 kDa N-terminal fragment of *E. coli* GyrA, which includes the QRDR and the active-site tyrosine. This structure was solved by X-ray crystallography at 2.8 Å resolution and provides the molecular basis for understanding quinolone resistance mutations.

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## 3. Cellular Signaling Pathways & Molecular Function

### 3.1 Catalytic Cycle of DNA Supercoiling

DNA gyrase is the only type II topoisomerase capable of introducing negative supercoils into DNA. The catalytic cycle proceeds as follows:

1. **DNA binding**: The GyrA CTD wraps a segment of DNA (the "G-segment") around the enzyme. A second segment (the "T-segment") is captured by the ATPase domains of GyrB.
2. **Cleavage**: The active-site tyrosines of GyrA perform a transesterification reaction, creating a transient double-strand break in the G-segment with 4-base overhangs. The tyrosines become covalently attached to the 5′-phosphates.
3. **Strand passage**: ATP hydrolysis by GyrB drives a conformational change that opens the DNA-gate, allowing the T-segment to pass through the break.
4. **Religation**: The G-segment is religated, and the T-segment is released. The enzyme resets for another cycle.

Each cycle introduces two negative supercoils, reducing the linking number (ΔLk = −2) [1, 23].

### 3.2 Role in Replication, Transcription, and Recombination

Gyrase is essential for:
- **Replication**: It removes positive supercoils that accumulate ahead of the replication fork. In its absence, replication stalls, leading to cell death [24, 25].
- **Transcription**: Negative supercoiling facilitates promoter melting and [RNA polymerase](/knowledge/bioinformatics/rna-polymerase-structure-transcription-mechanisms) binding. Gyrase activity is required for the expression of many genes, including those involved in virulence and stress responses [26, 27].
- **Recombination**: Gyrase-mediated supercoiling influences the accessibility of recombination sites and the activity of site-specific recombinases [24, 28, 29].

### 3.3 Protein-Protein Interaction Networks

GyrA interacts with several proteins beyond GyrB:

- **GyrI (SbmC)**: A DNA gyrase inhibitor that binds to GyrA and blocks supercoiling activity. GyrI is induced under stress conditions and may serve as a regulatory checkpoint [30].
- **MurI (glutamate racemase)**: In *M. tuberculosis*, MurI binds to GyrA and inhibits its DNA-binding activity, linking cell wall synthesis to DNA topology [1].
- **CcdB (F plasmid toxin)**: CcdB poisons DNA gyrase by trapping the cleavage complex, leading to double-strand breaks and cell death. GyrA mutations that suppress CcdB toxicity have been mapped to the QRDR [2, 24].
- **RcGTA (gene transfer agent)**: In *Rhodobacter capsulatus*, gyrase inhibitors increase the frequency of RcGTA-mediated horizontal gene transfer, suggesting a link between DNA topology and phage-like particle production [3].

### 3.4 Regulatory Feedback Loops

The expression of `gyrA` is autoregulated by DNA supercoiling. When supercoiling is low (relaxed DNA), `gyrA` transcription is upregulated; when supercoiling is high, transcription is downregulated. This feedback loop is mediated by the sensitivity of the `gyrA` promoter to superhelical density and by the binding of FIS and IHF [12, 13]. Additionally, the SOS response, triggered by DNA damage, can downregulate `gyrA` expression to reduce the frequency of cleavage complexes [26].

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## 4. Pathogenic Hotspot Mutations & Clinical Differentials

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

The QRDR is a highly conserved region of GyrA (residues 67–106 in *E. coli*) that forms the quinolone-binding pocket. Quinolones stabilize the cleavage complex by intercalating between the DNA bases and the active-site tyrosines, preventing religation. Mutations in the QRDR reduce drug binding affinity, allowing the enzyme to complete its catalytic cycle despite the presence of the antibiotic.

### 4.2 Common Mutations and Their Phenotypes

| **Mutation** | **Organism** | **Phenotype** | **Reference** |
| :--- | :--- | :--- | :--- |
| Ser83Leu | *E. coli* | High-level ciprofloxacin resistance (MIC ≥ 32 µg/mL) | [18, 19, 20, 21] |
| Ser83Trp | *E. coli* | High-level resistance; reduced fitness | [22] |
| Asp87Asn | *E. coli* | High-level resistance; often co-occurs with Ser83Leu | [18, 21] |
| Asp87Gly | *E. coli* | Moderate resistance; nalidixic acid resistance | [22] |
| Ser83Phe | *P. aeruginosa* | High-level fluoroquinolone resistance | [2, 3, 4, 5] |
| Thr83Ile | *C. jejuni* | Ciprofloxacin resistance (MIC ≥ 16 µg/mL) | [6] |
| Asp87Tyr | *S. pneumoniae* | Fluoroquinolone resistance; primary target in Gram-positives | [7, 8] |
| Ser91Phe | *N. gonorrhoeae* | Ciprofloxacin resistance; diagnostic target | [7, 8, 9] |
| Ser91Tyr | *N. meningitidis* | Ciprofloxacin resistance; clonal complex CC4821 | [10, 11] |
| Asp95Gly | *M. tuberculosis* | Ofloxacin resistance | [10, 12] |

### 4.3 Double Mutations and Synergistic Effects

Double mutations within the QRDR (e.g., Ser83Leu + Asp87Asn in *E. coli*) are associated with higher MICs than single mutations. The combination of mutations alters the electrostatic and steric properties of the binding pocket, further reducing quinolone affinity [13, 21]. In *K. pneumoniae*, double mutations in `gyrA` and `parC` (topoisomerase IV) are required for high-level fluoroquinolone resistance [4].

### 4.4 Mutations Outside the QRDR

Mutations outside the QRDR can also contribute to resistance or modulate fitness:

- **GyrA C-terminal domain mutations**: These affect DNA wrapping and supercoiling efficiency but are rarely associated with quinolone resistance [14].
- **GyrB mutations**: Mutations in the ATPase domain of GyrB (e.g., Asp426Asn) can confer low-level resistance and compensate for gyrA mutations [10, 15].
- **Intein insertions**: In mycobacteria, intein splicing is required for functional GyrA. Mutations that disrupt intein excision abolish enzyme activity [11, 16].

### 4.5 Clinical Differential Diagnostics

Detection of QRDR mutations is used clinically to predict fluoroquinolone susceptibility:

- **PCR-RFLP**: Mismatched PCR-restriction fragment length polymorphism assays can detect specific mutations in `gyrA` and `parC` [16].
- **DNA sequencing**: Sanger or next-generation sequencing of the QRDR provides definitive genotypic resistance data [7, 8].
- **Microarray**: Diagnostic DNA microarrays can simultaneously detect multiple QRDR mutations in clinical isolates [17].
- **Fluorogenic PCR**: Real-time PCR assays with fluorogenic probes can rapidly detect the Thr86Ile mutation in *C. jejuni* [6].

---

## 5. Host-Pathogen & Viral Interactions

### 5.1 Bacteriophage Interactions

DNA gyrase is exploited by several bacteriophages for their own replication:

- **Bacteriophage T5**: The growth of T5 requires host DNA gyrase. Inhibition of gyrase by quinolones blocks T5 DNA replication, demonstrating the dependence of the phage on host supercoiling machinery [18].
- **Bacteriophage T4**: The T4 topoisomerase is homologous to gyrase. The 52-kDa subunit of T4 topoisomerase shares sequence homology with GyrA, suggesting a common evolutionary origin [19].
- **RcGTA**: In *Rhodobacter capsulatus*, gyrase inhibitors increase the frequency of RcGTA-mediated gene transfer. This suggests that DNA relaxation promotes the production or release of gene transfer agents, facilitating horizontal gene transfer [3].

### 5.2 Plasmid Toxin-Antitoxin Systems

The F plasmid encodes the CcdB toxin, which poisons DNA gyrase by trapping the cleavage complex. CcdB binds to the GyrA subunit at the DNA-gate, stabilizing the covalent enzyme-DNA intermediate and leading to double-strand breaks. The antitoxin CcdA neutralizes CcdB by forming a stable complex. Mutations in `gyrA` that confer resistance to CcdB map to the QRDR and the tower domain, highlighting the overlap between quinolone and toxin binding sites [2, 24].

### 5.3 Mycobacterial Inteins and Host Immunity

In *Mycobacterium tuberculosis* and *M. leprae*, `gyrA` contains inteins that are spliced out post-translationally. These inteins are not present in human proteins, making them potential targets for antimicrobial therapy. Peptide nucleic acids (PNAs) targeting the intein-encoding region of `gyrA` have been shown to kill *M. smegmatis* in culture and in infected macrophages [20].

---

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

### 6.1 Quinolones and Fluoroquinolones

Quinolones are the primary class of drugs targeting GyrA. They are classified into generations based on their spectrum of activity:

- **First generation**: Nalidixic acid, oxolinic acid (limited to urinary tract infections).
- **Second generation**: Ciprofloxacin, norfloxacin, ofloxacin (broad-spectrum).
- **Third generation**: Levofloxacin, sparfloxacin (enhanced Gram-positive activity).
- **Fourth generation**: Moxifloxacin, trovafloxacin (anaerobic coverage).

Fluoroquinolones (FQs) bind to the QRDR of GyrA and the analogous region of ParC (topoisomerase IV). In Gram-negative bacteria, GyrA is the primary target; in Gram-positive bacteria, ParC is the primary target [8, 21]. FQ resistance arises primarily through QRDR mutations, with efflux pumps and plasmid-mediated resistance (e.g., Qnr proteins) playing secondary roles [13, 22].

### 6.2 Aminocoumarins

Aminocoumarin antibiotics (e.g., novobiocin, coumermycin A1) target the ATPase domain of GyrB, not GyrA. However, inhibition of GyrB indirectly affects GyrA function by preventing ATP hydrolysis and strand passage. Aminocoumarins have been used to study the role of supercoiling in gene expression and the SOS response [26].

### 6.3 Investigational Compounds and Novel Therapies

- **Zoliflodacin**: A spiropyrimidinetrione that inhibits DNA gyrase by a mechanism distinct from quinolones. It is currently in clinical trials for the treatment of uncomplicated gonorrhea. Resistance to zoliflodacin can arise through mutations in `gyrA` and `gyrB` [7].
- **Gepotidacin**: A triazaacenaphthylene that also targets GyrA and ParC but binds to a different site than quinolones. It is in Phase III trials for uncomplicated urinary tract infections and gonorrhea.
- **Peptide Nucleic Acids (PNAs)**: Antisense PNAs targeting `gyrA` mRNA have shown bactericidal activity against *M. smegmatis* [20].
- **Ciprofloxacin analogues**: Machine learning and molecular dynamics studies have identified novel ciprofloxacin analogues with improved binding affinity to mutant GyrA proteins [23].

### 6.4 Resistance Surveillance and Diagnostic Testing

Genotypic resistance testing for `gyrA` mutations is increasingly used to guide therapy:

- **Cepheid Xpert® CT/NG**: This assay can detect *N. gonorrhoeae* and, in research settings, has been adapted to genotype `gyrA` codon 91 to predict ciprofloxacin susceptibility [8].
- **Whole-genome sequencing (WGS)**: WGS provides comprehensive data on `gyrA` mutations and other resistance determinants, enabling precision antimicrobial therapy [7, 9].

---

## 7. Bioinformatic Resources & Database Accessions

| **Database** | **Accession / Identifier** | **Description** |
| :--- | :--- | :--- |
| NCBI Gene | 947762 (*E. coli* K-12) | Gene-specific information, genomic context, and expression data |
| Ensembl Bacteria | EB_ECOLI: b3690 | Genome browser view and comparative genomics |
| UniProtKB | P0AES4 | Protein sequence, function, and post-translational modifications |
| RCSB PDB | 1AB4 | 3D structure of the N-terminal domain of GyrA |
| Gene Ontology (GO) | GO:0003918 (DNA topoisomerase type II (ATP-hydrolyzing) activity); GO:0006265 (DNA topological change) | Functional annotation |
| BioGRID | 851842 | Protein-protein interactions |
| STRING | 511145.b3690 | Protein interaction networks |
| ClinVar | N/A (bacterial gene) | Human clinical variants not applicable |
| CARD (Comprehensive Antibiotic Resistance Database) | gyrA | Resistance gene ontology and mutation data |

---

## 8. Mermaid Diagram: GyrA-Mediated Quinolone Resistance Pathway

```mermaid
flowchart TD
    A["Quinolone antibiotic"] --> B{"Binds to GyrA QRDR"}
    B -->|"Wild-type GyrA"| C["Cleavage complex stabilized"]
    C --> D["Double-strand break"]
    D --> E["Cell death"]
    
    B -->|"Mutant GyrA (e.g., Ser83Leu)"| F["Reduced drug binding"]
    F --> G["Cleavage complex not stabilized"]
    G --> H["DNA religation proceeds"]
    H --> I["Cell survival"]
    I --> J["Resistance phenotype"]
    
    J --> K["Clinical treatment failure"]
    K --> L["Alternative antibiotics required"]
    
    M["Efflux pumps"] --> N["Reduced intracellular drug concentration"]
    N --> I
    
    O["Plasmid-mediated Qnr"] --> P["GyrA protection"]
    P --> I
```

---

## 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)
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## References

[1] Kong Hai-shen. "Emergence of novel variants of DNA gyrase subunit A gyrA gene in drug-resistant Enterobacter aerogenes." 2013. URL: https://www.semanticscholar.org/paper/fe79cbca310f99db6500f86a186f02a915f7ffd5

[2] Mitsuru Sada, Hirokazu Kimura, Norika Nagasawa, Mao Akagawa, Kaori Okayama, T. Shirai, Soyoka Sunagawa, R. Kimura, T. Saraya, H. Ishii, Daisuke Kurai, T. Tsugawa, Atsuyoshi Nishina, H. Tomita, Mitsuaki Okodo, Shinichiro Hirai, A. Ryo, Taisei Ishioka, K. Murakami. "Molecular Evolution of the Pseudomonas aeruginosa DNA Gyrase gyrA Gene." *Microorganisms*, 2022. URL: https://www.semanticscholar.org/paper/f03b1eda92afd10ff6dd89b571923c878614de81

[3] Stephen L. Swanberg, James C. Wang. "Cloning and sequencing of the Escherichia coli gyrA gene coding for the A subunit of DNA gyrase." *Journal of Molecular Biology*, 1987. URL: https://www.semanticscholar.org/paper/2182a55d8adf2755e9d1658fdf9b3a9f7473d6bb

[4] Amar Kureishi, M. Jonathan, Diver, Brenda Beckthold, Tineke, Schollaardt, L. E. Bryan. "Cloning and nucleotide sequence of Pseudomonas aeruginosa DNA gyrase gyrA gene from strain PAO1 and quinolone-resistant clinical isolates." *Antimicrobial Agents and Chemotherapy*, 1994. URL: https://www.semanticscholar.org/paper/390e9e447ed989c28c9610185c05626da2dcdc1a

[5] C. Bébéar, O. Grau, A. Charron, H. Renaudin, D. Gruson, C. Bébéar. "Cloning and Nucleotide Sequence of the DNA Gyrase (gyrA) Gene from Mycoplasma hominis and Characterization of Quinolone-Resistant Mutants Selected In Vitro with Trovafloxacin." *Antimicrobial Agents and Chemotherapy*, 2000. URL: https://www.semanticscholar.org/paper/1dd46987ea7b5bcc7d69a33ac2eeeb9ae06734d2

[6] T. Miki, J. Park, K. Nagao, N. Murayama, T. Horiuchi. "Control of segregation of chromosomal DNA by sex factor F in Escherichia coli. Mutants of DNA gyrase subunit A suppress letD (ccdB) product growth inhibition." *Journal of Molecular Biology*, 1992. URL: https://www.semanticscholar.org/paper/7e46a207c19c702119b6624404dd54c3d69cb74f

[7] Rachel Bernelot-Moens, J. Beatty. "DNA Gyrase Inhibitors Increase the Frequency of Bacteriophage-like RcGTA-Mediated Gene Transfer in Rhodobacter capsulatus." *Genes*, 2022. URL: https://www.semanticscholar.org/paper/331ad21ea59c4168ecb6f3fd02079ff2206488e3

[8] P. Behzadi, E. Behzadi, M. Moghaddam, A. Najafi, R. Ranjbar. "In Silico Analysis of Amino acid Substitutions in DNA gyrase subunit A of Fluoroquinolone Resistant P. aeruginosa TOHO Strains, A Glance on Antibiotic Development." 2014. URL: https://www.semanticscholar.org/paper/8bf10ee1fc466181dac6018a3ee8c3962c340fde

[9] D. Balas, Esteban Fernández-Moreira, A. G. de la Campa. "Molecular Characterization of the Gene Encoding the DNA Gyrase A Subunit of Streptococcus pneumoniae." *Journal of Bacteriology*, 1998. URL: https://www.semanticscholar.org/paper/b19c3fa9be46ec019f3a25404fb449b428187be4

[10] Kusum Mehla, Jayashree Ramana. "Structural signature of Ser83Leu and Asp87Asn mutations in DNA gyrase from enterotoxigenic Escherichia coli and impact on quinolone resistance." *Gene*, 2016. URL: https://www.semanticscholar.org/paper/df8083a302089b01d5247863f2107a4238ad1694

[11] Rosario Muñoz, A. G. D. L. Campa. "ParC subunit of DNA topoisomerase IV of Streptococcus pneumoniae is a primary target of fluoroquinolones and cooperates with DNA gyrase A subunit in forming resistance phenotype." *Antimicrobial Agents and Chemotherapy*, 1996. URL: https://www.semanticscholar.org/paper/8e810421494893c7bee39d5412dab3990a3a6441

[12] T. Deguchi, A. Fukuoka, M. Yasuda, Masahiro Nakano, S. Ozeki, E. Kanematsu, Y. Nishino, Satoshi Ishihara, Yoshihito Ban, Yukimichi Kawada. "Alterations in the GyrA subunit of DNA gyrase and the ParC subunit of topoisomerase IV in quinolone-resistant clinical isolates of Klebsiella pneumoniae." *Antimicrobial Agents and Chemotherapy*, 1997. URL: https://www.semanticscholar.org/paper/380b0ccc6b8224b97640e0afba58f22323eb06d0

[13] Mohd Ashraf Dar, Atul Sharma, Neelima Mondal, S. Dhar. "Molecular Cloning of Apicoplast-Targeted Plasmodium falciparum DNA Gyrase Genes: Unique Intrinsic ATPase Activity and ATP-Independent Dimerization of PfGyrB Subunit." *Eukaryotic Cell*, 2007. URL: https://www.semanticscholar.org/paper/5de31249372938f03907e4af27c543b8a75c03b1

[14] Kazumasa Yokoyama, Hyun Kim, T. Mukai, M. Matsuoka, C. Nakajima, Yasuhiko Suzuki. "Impact of Amino Acid Substitutions in B Subunit of DNA Gyrase in Mycobacterium leprae on Fluoroquinolone Resistance." *PLoS Neglected Tropical Diseases*, 2012. URL: https://www.semanticscholar.org/paper/05170da9a18c94bf033c1b45a17b16e4e42554ed

[15] M. E. Cullen, A. Wyke, R. Kuroda, L. Fisher. "Cloning and characterization of a DNA gyrase A gene from Escherichia coli that confers clinical resistance to 4-quinolones." *Antimicrobial Agents and Chemotherapy*, 1989. URL: https://www.semanticscholar.org/paper/6eab79b7341290e1128ef26f6663f80e4b8e01da

[16] S. Ostadhadi, M. Rashidi, Jalal Maradeneh, Vahid Nikoui. "Involvement of Mutation in Serine 83 of Quinolone Resistance-Determining Region of gyrA Gene in Resistance to Ciprofloxacin in Escherichia Coli." 2019. URL: https://www.semanticscholar.org/paper/6e19b4e440740e56fc2740a1f379ed36f4381d6d

[17] Pan Zhao, Aiyu Zhang, B. Zhu, Li Xu, Z. Shao. "Genetic diversity and characteristics of gyrA gene in Neisseria spp." 2019. URL: https://www.semanticscholar.org/paper/c56a98d045becbc5a0bd23f5d3ea73bd270a12b0

[18] Pamela G. Jones, R. Krah, S. Tafuri, A. Wolffe. "DNA gyrase, CS7.4, and the cold shock response in Escherichia coli." *Journal of Bacteriology*, 1992. URL: https://www.semanticscholar.org/paper/ff0101ccafa50114b7f35832b7ec5bd7584f7002

[19] B. Frasão, V. M. Medeiros, A. V. Barbosa, W. S. Aguiar, F. F. Santos, D. C. Abreu, M. Clementino, M. H. C. Aquino. "Detection of fluoroquinolone resistance by mutation in gyrA gene of Campylobacter spp. isolates from broiler and laying (Gallus gallus domesticus) hens, from Rio de Janeiro State, Brazil." 2015. URL: https://www.semanticscholar.org/paper/25a620d0beb7db679b5d0644616280d1de85f79a

[20] Mikiro Hayashi, K. Tabata. "Metabolic Engineering for l-Glutamine Overproduction by Using DNA Gyrase Mutations in Escherichia coli." *Applied and Environmental Microbiology*, 2013. URL: https://www.semanticscholar.org/paper/320157dcb79cc93154daeb3781e01aaec0f2dc90

[21] Md. Javed Foysal, M. Rahman, M. F. Rabbee, Md. Nazmul Hossain, R. Mahmud, Md. Julhasur Rahman, M. F. Miah, K. Islam. "Identification and Assay of Putative Virulence Properties of Escherichia coli gyrase Subunit A and B among Hospitalized UTI Patients in Bangladesh." 2013. URL: https://www.semanticscholar.org/paper/a519673129f9d3afccdb3a628e7a8111c898d946

[22] P. Brown, C. Peebles, N. Cozzarelli. "A topoisomerase from Escherichia coli related to DNA gyrase." *Proceedings of the National Academy of Sciences of the United States of America*, 1979. URL: https://www.semanticscholar.org/paper/6eba24da55a4c5ed0254e93a145ccd3ba5bb340f

[23] S. W. Knight, D. Samuels. "Natural synthesis of a DNA‐binding protein from the C‐terminal domain of DNA gyrase A in Borrelia burgdorferi." *EMBO Journal*, 1999. URL: https://www.semanticscholar.org/paper/3f67d36749602a7519d6aca2f168c3b8f1613f75

[24] Max Maurin, Chantal Abergel, Didier Raoult. "DNA Gyrase-Mediated Natural Resistance to Fluoroquinolones in Ehrlichia spp." *Antimicrobial Agents and Chemotherapy*, 2001. URL: https://www.semanticscholar.org/paper/5b93b01b23f6882f7f9f129c5529b9706efa624e

[25] Ying Wang, W. M. Huang, D. Taylor. "Cloning and nucleotide sequence of the Campylobacter jejuni gyrA gene and characterization of quinolone resistance mutations." *Antimicrobial Agents and Chemotherapy*, 1993. URL: https://www.semanticscholar.org/paper/2d87dcfd3d86bd601f117c8dc4e7478f7d295700

[26] M. Yonezawa, M. Takahata, N. Matsubara, Yasuo Watanabe, Hirokazu Narita. "DNA gyrase gyrA mutations in quinolone-resistant clinical isolates of Pseudomonas aeruginosa." *Antimicrobial Agents and Chemotherapy*, 1995. URL: https://www.semanticscholar.org/paper/cf0ad35c1964657253c7d61839af4e7c156c6e5c

[27] S. Ostadhadi, M. Rashidi, Samira Zolfaghari, J. Mardaneh, Vahid Nikoui. "The involvement of mutation in the serine 83 of quinolone resistant determining regions of the GyrA Gene in resistance to ciprofloxacin in Escherichia coli." 2016. URL: https://www.semanticscholar.org/paper/50fe132fe3cfe756e4250f7b34e7e9320002d817

[28] Sugopa Sengupta, Meera Shah, V. Nagaraja. "Glutamate racemase from Mycobacterium tuberculosis inhibits DNA gyrase by affecting its DNA-binding." *Nucleic Acids Research*, 2006. URL: https://www.semanticscholar.org/paper/564016f0e886a3896821659050bbb4113c20860e

[29] S. Brockbank, P. T. Barth. "Cloning, sequencing, and expression of the DNA gyrase genes from Staphylococcus aureus." *Journal of Bacteriology*, 1993. URL: https://www.semanticscholar.org/paper/0bea4ed660997ec6c44a5d9387285a407d8aa5f9

[30] J. Heddle, T. Lu, Xilin Zhao, K. Drlica, A. Maxwell. "gyrB-225, a mutation of DNA gyrase that compensates for topoisomerase I deficiency: investigation of its low activity and quinolone hypersensitivity." *Journal of Molecular Biology*, 2001. URL: https