title: DevR (DosR) mimetic peptides impair transcriptional regulation and survival of Mycobacterium tuberculosis under hypoxia by inhibiting the autokinase activity of DevS sensor kinase.
abstract: BACKGROUND
  Two-component systems have emerged as compelling targets for antibacterial drug design for a number of reasons including the distinct histidine phosphorylation property of their constituent sensor kinases. The DevR-DevS/DosT two component system of Mycobacterium tuberculosis (M. tb) is essential for survival under hypoxia, a stress associated with dormancy development in vivo. In the present study a combinatorial peptide phage display library was screened for DevS histidine kinase interacting peptides with the aim of isolating inhibitors of DevR-DevS signaling.
  
  
  RESULTS
  DevS binding peptides were identified from a phage display library after three rounds of panning using DevS as bait. The peptides showed sequence similarity with conserved residues in the N-terminal domain of DevR and suggested that they may represent interacting surfaces between DevS and DevR. Two DevR mimetic peptides were found to specifically inhibit DevR-dependent transcriptional activity and restrict the hypoxic survival of M. tb. The mechanism of peptide action is majorly attributed to an inhibition of DevS autokinase activity.
  
  
  CONCLUSIONS
  These findings demonstrate that DevR mimetic peptides impede DevS activation and that intercepting DevS activation at an early step in the signaling cascade impairs M. tb survival in a hypoxia persistence model.
authors.forename: Kohinoor
authors.initials: K
authors.lastname: Kaur
authors.forename: Neetu Kumra
authors.initials: NK
authors.lastname: Taneja
authors.forename: Sakshi
authors.initials: S
authors.lastname: Dhingra
authors.affiliation: Department of Biotechnology, All India Institute of Medical Sciences, New Delhi, India. jstyagi@gmail.com.
authors.forename: Jaya S
authors.initials: JS
authors.lastname: Tyagi
mesh_terms: D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D040761:Biomimetic Materials / Q000378:metabolism*; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects*; D050296:Microbial Viability / Q000187:drug effects*; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology; D010100:Oxygen / Q000378:metabolism; D019151:Peptide Library; D010455:Peptides / Q000378:metabolism; D006656:Protamine Kinase / Q000037:antagonists & inhibitors*; D011494:Protein Kinases / Q000378:metabolism*; D013312:Stress, Physiological
chemical_list: D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; C542863:DosR protein, Mycobacterium tuberculosis; D004791:Enzyme Inhibitors; D019151:Peptide Library; D010455:Peptides; D011494:Protein Kinases; C506260:DevS protein, Mycobacterium tuberculosis; D006656:Protamine Kinase; D010100:Oxygen