Evolution of the antibiotic resistance protein, FosA, is linked to a catalytically promiscuous progenitor.
The fosfomycin (1) resistance proteins FosA and FosX in pathogenic microorganisms are related to a catalytically promiscuous progenitor encoded in a phn operon in Mesorhizobium loti. The mlr3345 gene product (FosX(Ml)) from M. loti has a very low epoxide hydrolase activity and even lower glutathione transferase activity toward 1 and does not confer resistance to the antibiotic. In vitro homologous recombination of the mlr3345 and pa1129 genes (a fosA gene from Pseudomonas aeruginosa that does confer robust resistance to 1) produces recombinant proteins that confer resistance to 1 and indicate that the FosA resistance proteins are functionally and genetically related to mlr3345.
Brown
Daniel W
DW
Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37232-0146, USA.
Schaab
Matthew R
MR
Birmingham
William R
WR
Armstrong
Richard N
RN
D020561:Alphaproteobacteria / Q000187:drug effects / Q000201:enzymology / Q000235:genetics*; D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D002384:Catalysis; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004352:Drug Resistance, Microbial / Q000235:genetics*; D019143:Evolution, Molecular; D005578:Fosfomycin / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D005578:Fosfomycin; D005978:Glutathione