Molecule Information

General Information of the Molecule (ID: Mol01030)

• Name: Outer membrane porin F (OMPF) ,Escherichia coli
• Synonyms: Outer membrane protein 1A; Outer membrane protein B; Outer membrane protein F; Outer membrane protein IA; Porin OmpF; cmlB; coa; cry; tolF; b0929; JW0912
• Molecule Type: Protein
• Gene Name: ompF
• Gene ID: 66670795
• Sequence:
  MMKRNILAVIVPALLVAGTANAAEIYNKDGNKVDLYGKAVGLHYFSKGNGENSYGGNGDM
  TYARLGFKGETQINSDLTGYGQWEYNFQGNNSEGADAQTGNKTRLAFAGLKYADVGSFDY
  GRNYGVVYDALGYTDMLPEFGGDTAYSDDFFVGRVGGVATYRNSNFFGLVDGLNFAVQYL
  GKNERDTARRSNGDGVGGSISYEYEGFGIVGAYGAADRTNLQEAQPLGNGKKAEQWATGL
  KYDANNIYLAANYGETRNATPITNKFTNTSGFANKTQDVLLVAQYQFDFGLRPSIAYTKS
  KAKDVEGIGDVDLVNYFEVGATYYFNKNMSTYVDYIINQIDSDNKLGVGSDDTVAVGIVY
  QF
• Function: Forms pores that allow passive diffusion of small molecules across the outer membrane.
• Uniprot ID: OMPF_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

  IDUE: Irregularity in Drug Uptake and Drug Efflux

Drug Resistance Data Categorized by Drug

Approved Drug(s) 2 drug(s) in total

Cefepime

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Escherichia coli infection [1]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Resistant Drug: Cefepime
• Molecule Alteration: Missense mutation; p.G119D
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Enterobacter cloacae strain 201-RevM3; 550
• In Vitro Model: Escherichia coli strain Ak101; 562
• In Vitro Model: Escherichia coli strain BZB1107; 562
• In Vitro Model: Escherichia coli strain DH5alpha mutS; 668369
• Experiment for Molecule Alteration: SDS-PAGE assay
• Experiment for Drug Resistance: Twofold dilutions assay
• Mechanism Description: Substitutions G119D and G119E, inserting a protruding acidic side chain into the pore, decreased cephalosporin and colicin susceptibilities. Cefepime diffusion was drastically altered by these mutations. Conversely, substitutions R132A and R132D, changing a residue located in the positively charged cluster, increased the rate of cephalosporin uptake without modifying colicin sensitivity. Modelling approaches suggest that G119E generates a transverse hydrogen bond dividing the pore, while the two R132 substitutions stretch the channel size.

Disease Class: Escherichia coli infection [1]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Resistant Drug: Cefepime
• Molecule Alteration: Missense mutation; p.G119E
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Enterobacter cloacae strain 201-RevM3; 550
• In Vitro Model: Escherichia coli strain Ak101; 562
• In Vitro Model: Escherichia coli strain BZB1107; 562
• In Vitro Model: Escherichia coli strain DH5alpha mutS; 668369
• Experiment for Molecule Alteration: SDS-PAGE assay
• Experiment for Drug Resistance: Twofold dilutions assay
• Mechanism Description: Substitutions G119D and G119E, inserting a protruding acidic side chain into the pore, decreased cephalosporin and colicin susceptibilities. Cefepime diffusion was drastically altered by these mutations. Conversely, substitutions R132A and R132D, changing a residue located in the positively charged cluster, increased the rate of cephalosporin uptake without modifying colicin sensitivity. Modelling approaches suggest that G119E generates a transverse hydrogen bond dividing the pore, while the two R132 substitutions stretch the channel size.

Triclosan

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Escherichia coli infection [2]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Resistant Drug: Triclosan
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: E. coli IFN4; 562
• Experiment for Molecule Alteration: Microarray hybridization assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Concerning up-regulated porins and transporters (ompF, ompC, ykgG, ydjXYZ), they can either provide an efflux mechanism to export triclosan from the cells or accelerate the import of triclosan into the cytoplasm before the cell membrane is destabilized, thereby contributing to increasing the MICs of triclosan.

Investigative Drug(s) 1 drug(s) in total

Enacyloxin IIA

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Escherichia coli infection [3]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Resistant Drug: Enacyloxin IIA
• Molecule Alteration: Missense mutation; p.Q124K
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain LZ10; 562
• In Vitro Model: Escherichia coli strain LZ33L; 562
• In Vitro Model: Escherichia coli strain EV4; 562
• In Vitro Model: Escherichia coli strain EV4L; 562
• In Vitro Model: Escherichia coli strain LZ12; 562
• In Vitro Model: Escherichia coli strain LZ13; 562
• In Vitro Model: Escherichia coli strain LZ32; 562
• In Vitro Model: Escherichia coli strain LZ34L; 562
• In Vitro Model: Escherichia coli strain LZ40L; 562
• In Vitro Model: Escherichia coli strain PM816; 562
• Experiment for Molecule Alteration: PCR
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: For enacyloxin IIa we discovered four resistant elongation factor Tu (EF-Tu) species in Escherichia coli with the mutations Q124k, G316D, Q329H, and A375T. Among the mutant EF-Tus, three different resistance mechanisms can be distinguished: (i) by obstructing enacyloxin IIa binding to EF-Tu. GTP; (ii) by enabling the release of enacyloxin IIa after GTP hydrolysis; and (iii) by reducing the affinity of EF-Tu.GDP. enacyloxin IIa for aminoacyl-tRNA at the ribosomal A-site, which then allows the release of EF-Tu.GDP.enacyloxin IIa. Ala375 seems to contribute directly to enacyloxin IIa binding at the domain 1-3 interface of EF-Tu.GTP, a location that would easily explain the pleiotropic effects of enacyloxin IIa on the functioning of EF-Tu.

Disease Class: Escherichia coli infection [3]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Resistant Drug: Enacyloxin IIA
• Molecule Alteration: Missense mutation; p.G316D
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain LZ10; 562
• In Vitro Model: Escherichia coli strain LZ33L; 562
• In Vitro Model: Escherichia coli strain EV4; 562
• In Vitro Model: Escherichia coli strain EV4L; 562
• In Vitro Model: Escherichia coli strain LZ12; 562
• In Vitro Model: Escherichia coli strain LZ13; 562
• In Vitro Model: Escherichia coli strain LZ32; 562
• In Vitro Model: Escherichia coli strain LZ34L; 562
• In Vitro Model: Escherichia coli strain LZ40L; 562
• In Vitro Model: Escherichia coli strain PM816; 562
• Experiment for Molecule Alteration: PCR
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: For enacyloxin IIa we discovered four resistant elongation factor Tu (EF-Tu) species in Escherichia coli with the mutations Q124k, G316D, Q329H, and A375T. Among the mutant EF-Tus, three different resistance mechanisms can be distinguished: (i) by obstructing enacyloxin IIa binding to EF-Tu. GTP; (ii) by enabling the release of enacyloxin IIa after GTP hydrolysis; and (iii) by reducing the affinity of EF-Tu.GDP. enacyloxin IIa for aminoacyl-tRNA at the ribosomal A-site, which then allows the release of EF-Tu.GDP.enacyloxin IIa. Ala375 seems to contribute directly to enacyloxin IIa binding at the domain 1-3 interface of EF-Tu.GTP, a location that would easily explain the pleiotropic effects of enacyloxin IIa on the functioning of EF-Tu.

Disease Class: Escherichia coli infection [3]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Resistant Drug: Enacyloxin IIA
• Molecule Alteration: Missense mutation; p.Q329H
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain LZ10; 562
• In Vitro Model: Escherichia coli strain LZ33L; 562
• In Vitro Model: Escherichia coli strain EV4; 562
• In Vitro Model: Escherichia coli strain EV4L; 562
• In Vitro Model: Escherichia coli strain LZ12; 562
• In Vitro Model: Escherichia coli strain LZ13; 562
• In Vitro Model: Escherichia coli strain LZ32; 562
• In Vitro Model: Escherichia coli strain LZ34L; 562
• In Vitro Model: Escherichia coli strain LZ40L; 562
• In Vitro Model: Escherichia coli strain PM816; 562
• Experiment for Molecule Alteration: PCR
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: For enacyloxin IIa we discovered four resistant elongation factor Tu (EF-Tu) species in Escherichia coli with the mutations Q124k, G316D, Q329H, and A375T. Among the mutant EF-Tus, three different resistance mechanisms can be distinguished: (i) by obstructing enacyloxin IIa binding to EF-Tu. GTP; (ii) by enabling the release of enacyloxin IIa after GTP hydrolysis; and (iii) by reducing the affinity of EF-Tu.GDP. enacyloxin IIa for aminoacyl-tRNA at the ribosomal A-site, which then allows the release of EF-Tu.GDP.enacyloxin IIa. Ala375 seems to contribute directly to enacyloxin IIa binding at the domain 1-3 interface of EF-Tu.GTP, a location that would easily explain the pleiotropic effects of enacyloxin IIa on the functioning of EF-Tu.

Disease Class: Escherichia coli infection [3]

• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Resistant Drug: Enacyloxin IIA
• Molecule Alteration: Missense mutation; p.A375T
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain LZ10; 562
• In Vitro Model: Escherichia coli strain LZ33L; 562
• In Vitro Model: Escherichia coli strain EV4; 562
• In Vitro Model: Escherichia coli strain EV4L; 562
• In Vitro Model: Escherichia coli strain LZ12; 562
• In Vitro Model: Escherichia coli strain LZ13; 562
• In Vitro Model: Escherichia coli strain LZ32; 562
• In Vitro Model: Escherichia coli strain LZ34L; 562
• In Vitro Model: Escherichia coli strain LZ40L; 562
• In Vitro Model: Escherichia coli strain PM816; 562
• Experiment for Molecule Alteration: PCR
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: For enacyloxin IIa we discovered four resistant elongation factor Tu (EF-Tu) species in Escherichia coli with the mutations Q124k, G316D, Q329H, and A375T. Among the mutant EF-Tus, three different resistance mechanisms can be distinguished: (i) by obstructing enacyloxin IIa binding to EF-Tu. GTP; (ii) by enabling the release of enacyloxin IIa after GTP hydrolysis; and (iii) by reducing the affinity of EF-Tu.GDP. enacyloxin IIa for aminoacyl-tRNA at the ribosomal A-site, which then allows the release of EF-Tu.GDP.enacyloxin IIa. Ala375 seems to contribute directly to enacyloxin IIa binding at the domain 1-3 interface of EF-Tu.GTP, a location that would easily explain the pleiotropic effects of enacyloxin IIa on the functioning of EF-Tu.

References

• Ref 1: Substitutions in the eyelet region disrupt cefepime diffusion through the Escherichia coli OmpF channel. Antimicrob Agents Chemother. 2000 Feb;44(2):311-5. doi: 10.1128/AAC.44.2.311-315.2000.
• Ref 2: Signature gene expression profile of triclosan-resistant Escherichia coli. J Antimicrob Chemother. 2010 Jun;65(6):1171-7. doi: 10.1093/jac/dkq114. Epub 2010 Apr 21.
• Ref 3: Mutant EF-Tu species reveal novel features of the enacyloxin IIa inhibition mechanism on the ribosome. J Mol Biol. 1999 Dec 3;294(3):627-37. doi: 10.1006/jmbi.1999.3296.