A point mutation in cycA partially contributes to the D-cycloserine resistance trait of Mycobacterium bovis BCG vaccine strains.
In mycobacteria, CycA a D-serine, L- and D-alanine, and glycine transporter also functions in the uptake of D-cycloserine, an important second-line anti-tubercular drug. A single nucleotide polymorphism identified in the cycA gene of BCG was hypothesized to contribute to the increased resistance of Mycobacterium bovis bacillus Calmette-Guérin (BCG) to D-cycloserine compared to wild-type Mycobacterium tuberculosis or Mycobacterium bovis. Working along these lines, a merodiploid strain of BCG expressing Mycobacterium tuberculosis CycA was generated and found to exhibit increased susceptibility to D-cycloserine albeit not to the same extent as wild-type Mycobacterium tuberculosis or Mycobacterium bovis. In addition, recombinant Mycobacterium smegmatis strains expressing either Mycobacterium tuberculosis or Mycobacterium bovis CycA but not BCG CycA were rendered more susceptible to D-cycloserine. These findings support the notion that CycA-mediated uptake in BCG is impaired as a result of a single nucleotide polymorphism; however, the partial contribution of this impairment to D-cycloserine resistance suggests the involvement of additional genetic lesions in this phenotype.
École Polytechnique Fédérale de Lausanne, Global Health Institute, Lausanne, Switzerland. jeffrey.chen@epfl.ch
Jeffrey M
JM
Chen
Swapna
S
Uplekar
Stephen V
SV
Gordon
Stewart T
ST
Cole
D000595:Amino Acid Sequence; D026921:Amino Acid Transport Systems, Neutral / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000904:Antibiotics, Antitubercular / Q000494:pharmacology; D001500:BCG Vaccine / Q000276:immunology; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D003523:Cycloserine / Q000737:chemistry / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial / Q000235:genetics*; D055879:Gene Knock-In Techniques; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009163:Mycobacterium bovis / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D020102:Mycobacterium smegmatis / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide; D017433:Protein Structure, Secondary; D017386:Sequence Homology, Amino Acid; D027981:Symporters / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
D026921:Amino Acid Transport Systems, Neutral; D000904:Antibiotics, Antitubercular; D001500:BCG Vaccine; D001426:Bacterial Proteins; D027981:Symporters; D003523:Cycloserine