Drug Information

Drug (ID: DG00231) and It's Reported Resistant Information
Name
Kirromycin
Indication
In total 1 Indication(s)
Bacterial infection [ICD-11: 1A00-1C4Z]
Clinical trial
[1]
Structure
Drug Resistance Disease(s)
Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
Escherichia coli intestinal infection [ICD-11: 1A03]
[2], [3], [4]
Disease(s) with Resistance Information Validated by in-vivo Model for This Drug (1 diseases)
Actinomycetoma [ICD-11: 1C43]
[1]
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
Formula
C43H60N2O12
IsoSMILES
CC[C@H](C(=O)NC/C=C/C=C(\\C)/[C@H]([C@@H](C)[C@H]1[C@H]([C@H]([C@H](O1)/C=C/C=C/C=C(\\C)/C(=O)C2=C(C=CNC2=O)O)O)O)OC)[C@@]3([C@@H]([C@@H](C([C@@H](O3)/C=C/C=C\\C)(C)C)O)O)O
InChI
1S/C43H60N2O12/c1-9-11-13-21-31-42(6,7)38(50)39(51)43(54,57-31)28(10-2)40(52)44-23-17-16-19-26(4)36(55-8)27(5)37-35(49)34(48)30(56-37)20-15-12-14-18-25(3)33(47)32-29(46)22-24-45-41(32)53/h9,11-22,24,27-28,30-31,34-39,48-51,54H,10,23H2,1-8H3,(H,44,52)(H2,45,46,53)/b11-9-,14-12+,17-16+,20-15+,21-13+,25-18+,26-19+/t27-,28-,30-,31+,34+,35+,36-,37+,38+,39-,43-/m1/s1
InChIKey
HMSYAPGFKGSXAJ-PAHGNTJYSA-N
PubChem CID
135484176
TTD Drug ID
D0OG4A
Type(s) of Resistant Mechanism of This Drug
  ADTT: Aberration of the Drug's Therapeutic Target
Drug Resistance Data Categorized by Their Corresponding Diseases
ICD-01: Infectious/parasitic diseases
Click to Show/Hide the Resistance Disease of This Class
Escherichia coli intestinal infection [ICD-11: 1A03]
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Elongation factor Tu 1 (TUFA) [2], [3], [4]
Molecule Alteration Mutantion
p.G316D
 Molecule Info 
Resistant Disease Escherichia coli infection [ICD-11: 1A03.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Escherichia coli strain LZ10 562
Escherichia coli strain LBE 2045 562
Escherichia coli strain LZ31 562
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.
Key Molecule: Elongation factor Tu 2 (TUFB) [2], [3], [4]
Molecule Alteration Mutantion
p.G316D
 Molecule Info 
Resistant Disease Escherichia coli infection [ICD-11: 1A03.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Escherichia coli strain LZ10 562
Escherichia coli strain LBE 2045 562
Escherichia coli strain LZ31 562
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.
Key Molecule: Elongation factor Tu 1 (TUFA) [2], [3], [4]
Molecule Alteration Mutantion
p.A375T
 Molecule Info 
Resistant Disease Escherichia coli infection [ICD-11: 1A03.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Escherichia coli strain LZ10 562
Escherichia coli strain LBE 2045 562
Escherichia coli strain LZ31 562
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.
Key Molecule: Elongation factor Tu 2 (TUFB) [2], [3], [4]
Molecule Alteration Mutantion
p.A375T
 Molecule Info 
Resistant Disease Escherichia coli infection [ICD-11: 1A03.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Escherichia coli strain LZ10 562
Escherichia coli strain LBE 2045 562
Escherichia coli strain LZ31 562
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.
Key Molecule: Elongation factor Tu 1 (TUFA) [2], [3], [4]
Molecule Alteration Mutantion
p.A375V
 Molecule Info 
Resistant Disease Escherichia coli infection [ICD-11: 1A03.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Escherichia coli strain LZ10 562
Escherichia coli strain LBE 2045 562
Escherichia coli strain LZ31 562
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.
Key Molecule: Elongation factor Tu 2 (TUFB) [2], [3], [4]
Molecule Alteration Mutantion
p.A375V
 Molecule Info 
Resistant Disease Escherichia coli infection [ICD-11: 1A03.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Escherichia coli strain LZ10 562
Escherichia coli strain LBE 2045 562
Escherichia coli strain LZ31 562
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.
Key Molecule: Elongation factor Tu 1 (TUFA) [2], [3], [4]
Molecule Alteration Mutantion
p.Q124K
 Molecule Info 
Resistant Disease Escherichia coli infection [ICD-11: 1A03.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Escherichia coli strain LZ10 562
Escherichia coli strain LBE 2045 562
Escherichia coli strain LZ31 562
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.
Key Molecule: Elongation factor Tu 2 (TUFB) [2], [3], [4]
Molecule Alteration Mutantion
p.Q124K
 Molecule Info 
Resistant Disease Escherichia coli infection [ICD-11: 1A03.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Escherichia coli strain LZ10 562
Escherichia coli strain LBE 2045 562
Escherichia coli strain LZ31 562
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.
Actinomycetoma [ICD-11: 1C43]
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Elongation factor Tu (TUF) [1]
Molecule Alteration Missense mutation
p.T378A
 Molecule Info 
Resistant Disease Streptomyces cinnamoneus infection [ICD-11: 1C43.3]
 Disease Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Escherichia coli strain DH5alpha 668369
Escherichia coli strain JM109 83333
Streptomyces lividans strain 1326 1200984
Nocardia lactamdurans strain ATCC 27382 1913
Streptomyces cinnamoneus strain Tu89 53446
Streptomyces coelicolor strain M145 1902
Streptomyces glaucescens strain ETH 22794 1907
Experiment for
Molecule Alteration		 Southern hybridization assay
Mechanism Description The antibiotic kirromycin (kr) inhibits bacterial protein synthesis by binding to elongation factor Tu (EF-Tu). Streptomyces cinnamoneus and Nocardia lactamdurans, producers of antibiotics of the kr class, are known to possess an EF-Tu resistant to kr. Thr378, was mutated to the consensus Ala and the resulting mutant protein was sensitive to kr. Interestingly, it retained some activity (30% of the control) even at high kr concentrations.
References
Ref 1 Natural kirromycin resistance of elongation factor Tu from the kirrothricin producer Streptomyces cinnamoneus. Microbiology (Reading). 1997 Feb;143 ( Pt 2):617-624. doi: 10.1099/00221287-143-2-617.
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.

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