Abstract
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.
Highlights
Mycobacterium bovis bacillus Calmette-Guerin (BCG), is a live vaccine originally derived from a virulent isolate of Mycobacterium bovis, and has been used to immunize more than three billion people against tuberculosis [1]
Taking a genetic approach we show that BCG CycA is impaired for DCS uptake, the glycine 122 to serine substitution (G122S) change only partially contributes to DCS resistance in BCG, implicating additional mutations in this phenotype
We employed bioinformatics as well as two complementary genetic approaches to investigate the involvement of the non-synonymous single nucleotide polymorphism (nsSNP) in BCG cycA in DCS resistance
Summary
Mycobacterium bovis bacillus Calmette-Guerin (BCG), is a live vaccine originally derived from a virulent isolate of Mycobacterium bovis, and has been used to immunize more than three billion people against tuberculosis [1]. The protective efficacy imparted by BCG wanes significantly with time, and the molecular mechanism for this is poorly understood [1,2]. The mechanisms underlying the derivation of attenuated BCG from virulent M. bovis remain incompletely understood [1,2]. 13 strains of BCG with documented differences in attenuation and protective efficacy currently exist, and several of these are in use in various parts of the world [3,4]. The demonstration that loss of the RD1 locus by BCG was a key event leading to its attenuation, originated from such comparative genome studies [7]
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