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<i>Mycobacterium bovis</i> is the causative agent of tuberculosis in domestic and wild animal species and sometimes in humans, presenting variable degrees of pathogenicity. It is known that PknG is involved in the first steps of <i>Mycobacterium tuberculosis</i> macrophage infection and immune evasion. We questioned whether <i>M. bovis</i><i>pknG</i> genes were conserved among mycobacteria and if natural genetic modifications would affect its virulence. We discovered a single mutation at a catalytic domain (R242P) of one <i>M. bovis</i> isolate and established the relation between the presence of R242P mutation and enhanced <i>M. bovis</i> virulence. Here, we demonstrated that R242P mutation alters the PknG protein conformation to a more open ATP binding site cleft. It was observed that <i>M. bovis</i> with PknG mutation resulted in increased growth under stress conditions. In addition, infected macrophages by <i>M. bovis</i> (R242P) presented a higher bacterial load compared with <i>M. bovis</i> without the <i>pknG</i> mutation. Furthermore, using the mouse model of infection, animals infected with <i>M. bovis</i> (R242P) had a massive innate immune response migration to the lung that culminated with pneumonia, necrosis, and higher mortality. The PknG protein single point mutation in its catalytic domain did not reduce the bacterial fitness but rather increased its virulence.