Protein kinases PknA and PknB independently and coordinately regulate essential Mycobacterium tuberculosis physiologies and antimicrobial susceptibility.
PLoS Pathog
; 16(4): e1008452, 2020 04.
Article
in En
| MEDLINE
| ID: mdl-32255801
ABSTRACT
The Mycobacterium tuberculosis Ser/Thr protein kinases PknA and PknB are essential for growth and have been proposed as possible drug targets. We used a titratable conditional depletion system to investigate the functions of these kinases. Depletion of PknA or PknB or both kinases resulted in growth arrest, shortening of cells, and time-dependent loss of acid-fast staining with a concomitant decrease in mycolate synthesis and accumulation of trehalose monomycolate. Depletion of PknA and/or PknB resulted in markedly increased susceptibility to ß-lactam antibiotics, and to the key tuberculosis drug rifampin. Phosphoproteomic analysis showed extensive changes in protein phosphorylation in response to PknA depletion and comparatively fewer changes with PknB depletion. These results identify candidate substrates of each kinase and suggest specific and coordinate roles for PknA and PknB in regulating multiple essential physiologies. These findings support these kinases as targets for new antituberculosis drugs and provide a valuable resource for targeted investigation of mechanisms by which protein phosphorylation regulates pathways required for growth and virulence in M. tuberculosis.
Full text:
1
Database:
MEDLINE
Main subject:
Bacterial Proteins
/
Protein Serine-Threonine Kinases
/
Mycobacterium tuberculosis
/
Antitubercular Agents
Type of study:
Prognostic_studies
Limits:
Humans
Language:
En
Journal:
PLoS Pathog
Year:
2020
Type:
Article
Affiliation country:
United States