Comparative Analyses of Nonpathogenic, Opportunistic, and Totally Pathogenic Mycobacteria Reveal Genomic and Biochemical Variabilities and Highlight the Survival Attributes of Mycobacterium tuberculosis
Authors: Rahman Syed Asad , Singh Yadvir , Kohli Sakshi , Ahmad Javeed , Ehtesham Nasreen Z. , Tyagi Anil K. , Hasnain Seyed E. 
Published: November 2014

Mycobacterial evolution involves various processes, such as genome reduction, gene cooption, and critical gene acquisition. Our comparative genome size analysis of 44 mycobacterial genomes revealed that the nonpathogenic (NP) genomes were bigger than those of opportunistic (OP) or totally pathogenic (TP) mycobacteria, with the TP genomes being smaller yet variable in size—their genomic plasticity reflected their ability to evolve and survive under various environmental conditions. From the 44 mycobacterial species, 13 species, representing TP, OP, and NP, were selected for genomic-relatedness analyses. Analysis of homologous protein-coding genes shared between
Mycobacterium indicus pranii
(NP),
Mycobacterium intracellulare
ATCC 13950 (OP), and
Mycobacterium tuberculosis
H37Rv (TP) revealed that 4,995 (i.e., ~95%)
M. indicaus pranii
proteins have homology with
M. intracellulare
, whereas the homologies among
M. indicus pranii
,
M. intracellulare
ATCC 13950, and
M. tuberculosis
H37Rv were significantly lower. A total of 4,153 (~79%)
M. indicus pranii
proteins and 4,093 (~79%)
M. intracellulare
ATCC 13950 proteins exhibited homology with the
M. tuberculosis
H37Rv proteome, while 3,301 (~82%) and 3,295 (~82%)
M. tuberculosis
H37Rv proteins showed homology with
M. indicus pranii
and
M. intracellulare
ATCC 13950 proteomes, respectively. Comparative metabolic pathway analyses of TP/OP/NP mycobacteria showed enzymatic plasticity between
M. indicus pranii
(NP) and
M. intracellulare
ATCC 13950 (OP),
Mycobacterium avium
104 (OP), and
M. tuberculosis
H37Rv (TP).
Mycobacterium tuberculosis
seems to have acquired novel alternate pathways with possible roles in metabolism, host-pathogen interactions, virulence, and intracellular survival, and by implication some of these could be potential drug targets.

IMPORTANCE
The complete sequence analysis of
Mycobacterium indicus pranii
, a novel species of
Mycobacterium
shown earlier to have strong immunomodulatory properties and currently in use for the treatment of leprosy, places it evolutionarily at the point of transition to pathogenicity. With the purpose of establishing the importance of
M. indicus pranii
in providing insight into the virulence mechanism of tuberculous and nontuberculous mycobacteria, we carried out comparative genomic and proteomic analyses of 44 mycobacterial species representing nonpathogenic (NP), opportunistic (OP), and totally pathogenic (TP) mycobacteria. Our results clearly placed
M. indicus pranii
as an ancestor of the
M. avium
complex. Analyses of comparative metabolic pathways between
M. indicus pranii
(NP),
M. tuberculosis
(TP), and
M. intracellulare
(OP) pointed to the presence of novel alternative pathways in
M. tuberculosis
with implications for pathogenesis and survival in the human host and identification of new drug targets.