title: Protein kinase C-δ inhibitor, Rottlerin inhibits growth and survival of mycobacteria exclusively through Shikimate kinase.
abstract: The molecular bases of disease provide exceptional prospect to translate research findings into new drugs. Nevertheless, to develop new and novel chemical entities takes huge amount of time and efforts, mainly due to the stringent processes. Therefore, drug repurposing is one of such strategies which is being used in recent times to identify new pharmacophores. The essential first step in discovery of the specific inhibitor with low toxicity is the identification and elucidation of pathways exclusive to target pathogen. One such target is the shikimate pathway, which is essential for algae, higher plants, bacteria and fungi. Since, this enzyme system is absent in higher eukaryotes and in mammals, the enzymes involved in the pathway provide an attractive target for the development of potentially selective and non toxic antimicrobial agents. Since, so far there is no specific inhibitor which is able to restrain mycobacterial shikimate pathway; we expanded the use of a known kinase inhibitor; Rottlerin, in order to predict the prototype in discovering the specific molecules against this enzyme. For the first time we have shown that Rottlerin inhibits extracellular mycobacteria by affecting Shikimate Kinase (SK) and this effect is further enhanced during the intracellular infection due to the added effect of PKC- δ down-regulation. The molecular docking of Rottlerin with both the mycobacterial SKs, corroborated the inhibition data, and revealed that the effects of SK, in slow and in fast grower mycobacteria are due to the changes in affinity of binding with the drug.
authors: Division of Microbiology, CSIR-Central Drug Research Institute, Lucknow, 226031, India.
authors: Sapna
authors: S
authors: Pandey
authors: Division of Microbiology, CSIR-Central Drug Research Institute, Lucknow, 226031, India.
authors: Aditi
authors: A
authors: Chatterjee
authors: Division of Microbiology, CSIR-Central Drug Research Institute, Lucknow, 226031, India.
authors: Swati
authors: S
authors: Jaiswal
authors: Division of Molecular Structural Biology, CSIR-Central Drug Research Institute, Lucknow, 226031, India.
authors: Sanjay
authors: S
authors: Kumar
authors: Division of Molecular Structural Biology, CSIR-Central Drug Research Institute, Lucknow, 226031, India.
authors: Ravishankar
authors: R
authors: Ramachandran
authors: Division of Microbiology, CSIR-Central Drug Research Institute, Lucknow, 226031, India. Electronic address: kishore@cdri.res.in.
authors: Kishore K
authors: KK
authors: Srivastava
mesh_terms: D000098:Acetophenones / Q000737:chemistry / Q000494:pharmacology*; D001578:Benzopyrans / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D003001:Cloning, Molecular; D058492:Drug Repositioning; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D007700:Kinetics; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020102:Mycobacterium smegmatis / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D000098:Acetophenones; D001578:Benzopyrans; D047428:Protein Kinase Inhibitors; D011994:Recombinant Proteins; C085746:rottlerin; D017853:Phosphotransferases (Alcohol Group Acceptor); C022642:shikimate kinase; D051745:Protein Kinase C-delta
keywords: Mycobacteria; PKC-δ; Rottlerin; Shikimate kinase