Structure of the Tet Repressor-tetracycline Complex and Regulation of Antibiotic Resistance

Hinrichs, Winfried; Kisker, Caroline; Düvel, Martina; Muller, Alexander J.; Tovar, Karlheinz; Hillen, Wolfgang; Saenger, Wolfram

doi:10.1126/science.8153629

Cited by 399 publications

(417 citation statements)

References 43 publications

Supporting

Mentioning

393

Contrasting

Unclassified

Order By: Relevance

“…The resistance of Gram-negative bacteria against tetracyclines is frequently triggered by drug recognition of the Tet repressor. This enables expression of the resistance protein TetA, which is responsible for active efflux of tetracycline [34].The downregulation of this gene is in agreement with the wellestablished antimicrobial susceptibility of the B. cenocepacia D4 mutant [12].…”

Section: Cog Tk Category: Signal Transduction Mechanisms and Transcrisupporting

confidence: 56%

RND-4 efflux transporter gene deletion in Burkholderia cenocepacia J2315: a proteomic analysis

Gamberi

Rocchiccioli²,

Papaleo³

et al. 2013

J Proteome Sci Comput Biol

View full text Add to dashboard Cite

Background: The Burkholderia cenocepacia J2315 is Gram-negative bacterium that is a pathogen for cystic fibrosis (CF) patients. It displays a high-level of resistance to most antimicrobial drugs. In Gram-negative bacteria, the ResistanceNodulation-Cell Division (RND) transporter family has a poorly understood role in multidrug resistance. In a previous publication we analysed the RND-4 and RND-9 transporters by microarray analysis. The obtained results suggested that only RND-4 contributes to the antibiotic resistance. The aim of this study was to investigate the role of this efflux transporter from a proteomic point of view.

show abstract

Section: Cog Tk Category: Signal Transduction Mechanisms and Transcrisupporting

confidence: 56%

RND-4 efflux transporter gene deletion in Burkholderia cenocepacia J2315: a proteomic analysis

Gamberi

Rocchiccioli²,

Papaleo³

et al. 2013

J Proteome Sci Comput Biol

View full text Add to dashboard Cite

show abstract

“…The expression of this protein is regulated by the Tet repressor (TetR), which binds to the DNA and prevents the transcription of tetA 201. When tetracycline binds to TetR with the aid of Mg 2+ (Figure 44), such as when it binds to its ribosomal target, the conformation of TetR changes and transcription of the resistance genes take place 199, 201, 202…”

Section: Intervention At the Genetic Levelmentioning

confidence: 99%

Targeting Antibiotic Resistance

2016

View full text Add to dashboard Cite

Finding strategies against the development of antibiotic resistance is a major global challenge for the life sciences community and for public health. The past decades have seen a dramatic worldwide increase in human‐pathogenic bacteria that are resistant to one or multiple antibiotics. More and more infections caused by resistant microorganisms fail to respond to conventional treatment, and in some cases, even last‐resort antibiotics have lost their power. In addition, industry pipelines for the development of novel antibiotics have run dry over the past decades. A recent world health day by the World Health Organization titled “Combat drug resistance: no action today means no cure tomorrow” triggered an increase in research activity, and several promising strategies have been developed to restore treatment options against infections by resistant bacterial pathogens.

show abstract

“…16 This is evident through protein sequence alignment that residues 7-60 of Rv1219c possess 25%, 24%, and 31% amino acid identity to TetR, 17 QacR, 18 and Rv3066, 14 respectively. In addition, superimposition of the Ca atoms of this N-terminal region, between residues 7 and 60, with those of AcrR 19 and Rv3066 14 results in overall rms deviations of 3.1 and 3.2 Å .…”

Section: N-terminal Domainmentioning

confidence: 99%

Crystal structure of the transcriptional regulator Rv1219c of Mycobacterium tuberculosis

et al. 2014

View full text Add to dashboard Cite

The Rv1217c-Rv1218c multidrug efflux system, which belongs to the ATP-binding cassette superfamily, recognizes and actively extrudes a variety of structurally unrelated toxic chemicals and mediates the intrinsic resistance to these antimicrobials in Mycobacterium tuberculosis. The expression of Rv1217c-Rv1218c is controlled by the TetR-like transcriptional regulator Rv1219c, which is encoded by a gene immediately upstream of rv1218c. To elucidate the structural basis of Rv1219c regulation, we have determined the crystal structure of Rv1219c, which reveals a dimeric two-domain molecule with an entirely helical architecture similar to members of the TetR family of transcriptional regulators. The N-terminal domains of the Rv1219c dimer are separated by a large center-to-center distance of 64 Å . The C-terminal domain of each protomer possesses a large cavity. Docking of small compounds to Rv1219c suggests that this large cavity forms a multidrug binding pocket, which can accommodate a variety of structurally unrelated antimicrobial agents. The internal wall of the multidrug binding site is surrounded by seven aromatic residues, indicating that drug binding may be governed by aromatic stacking interactions. In addition, fluorescence polarization reveals that Rv1219c binds drugs in the micromolar range.

show abstract

Structure of the Tet Repressor-tetracycline Complex and Regulation of Antibiotic Resistance

Cited by 399 publications

References 43 publications

RND-4 efflux transporter gene deletion in Burkholderia cenocepacia J2315: a proteomic analysis

RND-4 efflux transporter gene deletion in Burkholderia cenocepacia J2315: a proteomic analysis

Targeting Antibiotic Resistance

Crystal structure of the transcriptional regulator Rv1219c of Mycobacterium tuberculosis

Contact Info

Product

Resources

About