Title |
PknB remains an essential and a conserved target for drug development in susceptible and MDR strains of M. Tuberculosis
|
---|---|
Published in |
Annals of Clinical Microbiology and Antimicrobials, August 2017
|
DOI | 10.1186/s12941-017-0234-9 |
Pubmed ID | |
Authors |
Anamika Gupta, Sudhir K. Pal, Divya Pandey, Najneen A. Fakir, Sunita Rathod, Dhiraj Sinha, S. SivaKumar, Pallavi Sinha, Mycal Periera, Shilpa Balgam, Gomathi Sekar, K. R. UmaDevi, Shampa Anupurba, Vijay Nema |
Abstract |
The Mycobacterium tuberculosis (M.tb) protein kinase B (PknB) which is now proved to be essential for the growth and survival of M.tb, is a transmembrane protein with a potential to be a good drug target. However it is not known if this target remains conserved in otherwise resistant isolates from clinical origin. The present study describes the conservation analysis of sequences covering the inhibitor binding domain of PknB to assess if it remains conserved in susceptible and resistant clinical strains of mycobacteria picked from three different geographical areas of India. A total of 116 isolates from North, South and West India were used in the study with a variable profile of their susceptibilities towards streptomycin, isoniazid, rifampicin, ethambutol and ofloxacin. Isolates were also spoligotyped in order to find if the conservation pattern of pknB gene remain consistent or differ with different spoligotypes. The impact of variation as found in the study was analyzed using Molecular dynamics simulations. The sequencing results with 115/116 isolates revealed the conserved nature of pknB sequences irrespective of their susceptibility status and spoligotypes. The only variation found was in one strains wherein pnkB sequence had G to A mutation at 664 position translating into a change of amino acid, Valine to Isoleucine. After analyzing the impact of this sequence variation using Molecular dynamics simulations, it was observed that the variation is causing no significant change in protein structure or the inhibitor binding. Hence, the study endorses that PknB is an ideal target for drug development and there is no pre-existing or induced resistance with respect to the sequences involved in inhibitor binding. Also if the mutation that we are reporting for the first time is found again in subsequent work, it should be checked with phenotypic profile before drawing the conclusion that it would affect the activity in any way. Bioinformatics analysis in our study says that it has no significant effect on the binding and hence the activity of the protein. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
United Kingdom | 3 | 38% |
Venezuela, Bolivarian Republic of | 1 | 13% |
Unknown | 4 | 50% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 7 | 88% |
Scientists | 1 | 13% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 53 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 10 | 19% |
Student > Ph. D. Student | 10 | 19% |
Student > Bachelor | 6 | 11% |
Student > Master | 5 | 9% |
Other | 3 | 6% |
Other | 7 | 13% |
Unknown | 12 | 23% |
Readers by discipline | Count | As % |
---|---|---|
Medicine and Dentistry | 11 | 21% |
Biochemistry, Genetics and Molecular Biology | 8 | 15% |
Immunology and Microbiology | 5 | 9% |
Agricultural and Biological Sciences | 4 | 8% |
Pharmacology, Toxicology and Pharmaceutical Science | 3 | 6% |
Other | 9 | 17% |
Unknown | 13 | 25% |