Molecule Information

General Information of the Molecule (ID: Mol00953)

• Name: Elongation factor Tu 2 (TUFB) ,Escherichia coli
• Synonyms: EF-Tu 2; Bacteriophage Q beta RNA-directed RNA polymerase subunit III; P-43; b3980; JW3943
• Molecule Type: Protein
• Gene Name: tufB
• Gene ID: 66672109
• Sequence:
  MSKEKFERTKPHVNVGTIGHVDHGKTTLTAAITTVLAKTYGGAARAFDQIDNAPEEKARG
  ITINTSHVEYDTPTRHYAHVDCPGHADYVKNMITGAAQMDGAILVVAATDGPMPQTREHI
  LLGRQVGVPYIIVFLNKCDMVDDEELLELVEMEVRELLSQYDFPGDDTPIVRGSALKALE
  GDAEWEAKILELAGFLDSYIPEPERAIDKPFLLPIEDVFSISGRGTVVTGRVERGIIKVG
  EEVEIVGIKETQKSTCTGVEMFRKLLDEGRAGENVGVLLRGIKREEIERGQVLAKPGTIK
  PHTKFESEVYILSKDEGGRHTPFFKGYRPQFYFRTTDVTGTIELPEGVEMVMPGDNIKMV
  VTLIHPIAMDDGLRFAIREGGRTVGAGVVAKVLS
• Function: This protein promotes the GTP-dependent binding of aminoacyl-tRNA to the A-site of ribosomes during protein biosynthesis.; FUNCTION: May play an important regulatory role in cell growth and in the bacterial response to nutrient deprivation.; FUNCTION: Plays a stimulatory role in trans-translation, binds tmRNA.
• Uniprot ID: EFTU2_ECOLI

Kingdom: N.A.
Phylum: Proteobacteria
Class: Gammaproteobacteria
Order: Enterobacterales
Family: Enterobacteriaceae
Genus: Escherichia
Species: Escherichia coli

Type(s) of Resistant Mechanism of This Molecule

  ADTT: Aberration of the Drug's Therapeutic Target

Drug Resistance Data Categorized by Drug

Investigative Drug(s) 3 drug(s) in total

Ge2270a

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Escherichia coli infection [1]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Resistant Drug: Ge2270a
• Molecule Alteration: Missense mutation; p.G257S
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain; 562
• Mechanism Description: The antibiotic GE2270A prevents stable complex formation between elongation factor Tu (EF-Tu) and aminoacyl-tRNA (aatRNA). In Escherichia coli we characterized two mutant EF-Tu species with either G257S or G275A that lead to high GE2270A resistance in poly(Phe) synthesis, which at least partially explains the high resistance of EF-Tu1 from GE2270A producer Planobispora rosea to its own antibiotic.

Disease Class: Escherichia coli infection [1]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Resistant Drug: Ge2270a
• Molecule Alteration: Missense mutation; p.G275A
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain; 562
• Mechanism Description: The antibiotic GE2270A prevents stable complex formation between elongation factor Tu (EF-Tu) and aminoacyl-tRNA (aatRNA). In Escherichia coli we characterized two mutant EF-Tu species with either G257S or G275A that lead to high GE2270A resistance in poly(Phe) synthesis, which at least partially explains the high resistance of EF-Tu1 from GE2270A producer Planobispora rosea to its own antibiotic.

Kirromycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Escherichia coli infection [2], [3], [4]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Resistant Drug: Kirromycin
• Molecule Alteration: Mutantion; p.G316D
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain LZ10; 562
• In Vitro Model: Escherichia coli strain LBE 2045; 562
• In Vitro Model: Escherichia coli strain LZ31; 562
• In Vitro Model: Escherichia coli strain MRE600; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: The mutant EF-Tu species G316D, A375T, A375V and Q124k, isolated by M13mp phage-mediated targeted mutagenesis, were studied. In this order the mutant EF-Tu species showed increasing resistance to the antibiotic as measured by poly(U)-directed poly(Phe) synthesis and intrinsic GTPase activities.The mutations result in two separate mechanisms of resistance to kirromycin. The first inhibits access of the antibiotic to its binding site on EF-TuGTP. A second mechanism exists on the ribosome, when mutant EF-Tu species release kirromycin and polypeptide chain elongation continues.

Disease Class: Escherichia coli infection [2], [3], [4]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Resistant Drug: Kirromycin
• Molecule Alteration: Mutantion; p.A375T
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain LZ10; 562
• In Vitro Model: Escherichia coli strain LBE 2045; 562
• In Vitro Model: Escherichia coli strain LZ31; 562
• In Vitro Model: Escherichia coli strain MRE600; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: The mutant EF-Tu species G316D, A375T, A375V and Q124k, isolated by M13mp phage-mediated targeted mutagenesis, were studied. In this order the mutant EF-Tu species showed increasing resistance to the antibiotic as measured by poly(U)-directed poly(Phe) synthesis and intrinsic GTPase activities.The mutations result in two separate mechanisms of resistance to kirromycin. The first inhibits access of the antibiotic to its binding site on EF-TuGTP. A second mechanism exists on the ribosome, when mutant EF-Tu species release kirromycin and polypeptide chain elongation continues.

Disease Class: Escherichia coli infection [2], [3], [4]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Resistant Drug: Kirromycin
• Molecule Alteration: Mutantion; p.A375V
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain LZ10; 562
• In Vitro Model: Escherichia coli strain LBE 2045; 562
• In Vitro Model: Escherichia coli strain LZ31; 562
• In Vitro Model: Escherichia coli strain MRE600; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: The mutant EF-Tu species G316D, A375T, A375V and Q124k, isolated by M13mp phage-mediated targeted mutagenesis, were studied. In this order the mutant EF-Tu species showed increasing resistance to the antibiotic as measured by poly(U)-directed poly(Phe) synthesis and intrinsic GTPase activities.The mutations result in two separate mechanisms of resistance to kirromycin. The first inhibits access of the antibiotic to its binding site on EF-TuGTP. A second mechanism exists on the ribosome, when mutant EF-Tu species release kirromycin and polypeptide chain elongation continues.

Disease Class: Escherichia coli infection [2], [3], [4]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Resistant Drug: Kirromycin
• Molecule Alteration: Mutantion; p.Q124K
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli strain LZ10; 562
• In Vitro Model: Escherichia coli strain LBE 2045; 562
• In Vitro Model: Escherichia coli strain LZ31; 562
• In Vitro Model: Escherichia coli strain MRE600; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: The mutant EF-Tu species G316D, A375T, A375V and Q124k, isolated by M13mp phage-mediated targeted mutagenesis, were studied. In this order the mutant EF-Tu species showed increasing resistance to the antibiotic as measured by poly(U)-directed poly(Phe) synthesis and intrinsic GTPase activities.The mutations result in two separate mechanisms of resistance to kirromycin. The first inhibits access of the antibiotic to its binding site on EF-TuGTP. A second mechanism exists on the ribosome, when mutant EF-Tu species release kirromycin and polypeptide chain elongation continues.

Pulvomycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Escherichia coli infection [5]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Resistant Drug: Pulvomycin
• Molecule Alteration: Missense mutation; p.R230C
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain LZ33L; 562
• In Vitro Model: Escherichiacoli strain EV4; 562
• In Vitro Model: Escherichiacoli strain LBE2040; 562
• In Vitro Model: Escherichiacoli strain LZ32L; 562
• In Vitro Model: Escherichiacoli strain LZ35L; 562
• In Vitro Model: Escherichiacoli strain LZ36L; 562
• In Vitro Model: Escherichiacoli strain LZ37L; 562
• In Vitro Model: Escherichiacoli strain MG1655; 511145
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Together with targeted mutagenesis of the tufA gene, conditions were found to overcome membrane impermeability, thereby allowing the selection of three mutants harbouring elongation factor (EF)-Tu Arg230-->Cys, Arg333-->Cys or Thr334-->Ala which confer pulvomycin resistance.Pulvomycin and kirromycin both act by specifically disturbing the allosteric changes required for the switch from EF-Tu-GTP to EF-Tu-GDP. The three-domain junction changes dramatically in the switch to EF-Tu.GDP; in EF-Tu.GDP this region forms an open hole. The two most highly resistant mutants, R230C and R333C, are part of an electrostatic network involving numerous residues.

Disease Class: Escherichia coli infection [5]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Resistant Drug: Pulvomycin
• Molecule Alteration: Missense mutation; p.R333C
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain LZ33L; 562
• In Vitro Model: Escherichiacoli strain EV4; 562
• In Vitro Model: Escherichiacoli strain LBE2040; 562
• In Vitro Model: Escherichiacoli strain LZ32L; 562
• In Vitro Model: Escherichiacoli strain LZ35L; 562
• In Vitro Model: Escherichiacoli strain LZ36L; 562
• In Vitro Model: Escherichiacoli strain LZ37L; 562
• In Vitro Model: Escherichiacoli strain MG1655; 511145
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Together with targeted mutagenesis of the tufA gene, conditions were found to overcome membrane impermeability, thereby allowing the selection of three mutants harbouring elongation factor (EF)-Tu Arg230-->Cys, Arg333-->Cys or Thr334-->Ala which confer pulvomycin resistance.Pulvomycin and kirromycin both act by specifically disturbing the allosteric changes required for the switch from EF-Tu-GTP to EF-Tu-GDP. The three-domain junction changes dramatically in the switch to EF-Tu.GDP; in EF-Tu.GDP this region forms an open hole. The two most highly resistant mutants, R230C and R333C, are part of an electrostatic network involving numerous residues.

Disease Class: Escherichia coli infection [5]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Resistant Drug: Pulvomycin
• Molecule Alteration: Missense mutation; p.T334A
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain LZ33L; 562
• In Vitro Model: Escherichiacoli strain EV4; 562
• In Vitro Model: Escherichiacoli strain LBE2040; 562
• In Vitro Model: Escherichiacoli strain LZ32L; 562
• In Vitro Model: Escherichiacoli strain LZ35L; 562
• In Vitro Model: Escherichiacoli strain LZ36L; 562
• In Vitro Model: Escherichiacoli strain LZ37L; 562
• In Vitro Model: Escherichiacoli strain MG1655; 511145
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Together with targeted mutagenesis of the tufA gene, conditions were found to overcome membrane impermeability, thereby allowing the selection of three mutants harbouring elongation factor (EF)-Tu Arg230-->Cys, Arg333-->Cys or Thr334-->Ala which confer pulvomycin resistance.Pulvomycin and kirromycin both act by specifically disturbing the allosteric changes required for the switch from EF-Tu-GTP to EF-Tu-GDP. The three-domain junction changes dramatically in the switch to EF-Tu.GDP; in EF-Tu.GDP this region forms an open hole. The two most highly resistant mutants, R230C and R333C, are part of an electrostatic network involving numerous residues.

References

• Ref 1: GE2270A-resistant mutations in elongation factor Tu allow productive aminoacyl-tRNA binding to EF-Tu.GTP.GE2270A complexes. J Mol Biol. 2000 Dec 15;304(5):995-1005. doi: 10.1006/jmbi.2000.4260.
• Ref 2: Inhibitory mechanisms of antibiotics targeting elongation factor Tu. Curr Protein Pept Sci. 2002 Feb;3(1):121-31. doi: 10.2174/1389203023380855.
• Ref 3: Mutant sequences in the rpsL gene of Escherichia coli B/r: mechanistic implications for spontaneous and ultraviolet light mutagenesis. Mol Gen Genet. 1992 Mar;232(1):89-96. doi: 10.1007/BF00299141.
• Ref 4: The structural and functional basis for the kirromycin resistance of mutant EF-Tu species in Escherichia coli. EMBO J. 1994 Oct 17;13(20):4877-85.
• Ref 5: Pulvomycin-resistant mutants of E.coli elongation factor Tu. EMBO J. 1994 Nov 1;13(21):5113-20.