Inhibition of NarL of Mycobacterium Tuberculosis: an in silico approach

Abstract

Mycobacterium tuberculosis (MTB) consumes nitrate as the alternate mechanism of respiration in the absence of oxygen, thus increasing its survival and virulence during latent stage of tuberculosis infection. NarL is a nitrate/nitrite response transcriptional regulatory protein of two-component signal transduction system which regulates nitrate reductase and formate dehydrogenase for MTB adaptation to anaerobic condition. Phosphorylation by sensor kinase (NarX) is the primary mechanism behind the activation of NarL although many response regulators get activated by small molecule phospho-donors in the absence of sensor kinase. Virtual screening was performed using Autodock suite for the compounds from ZINC database against NarL and potential inhibitors was identified to inhibit the activation of NarL by affecting its phosphorylation. Molecular dynamics simulation studies predicted the stability of 1-{1-[(3-nitrophenyl) methyl] piperidin-2-yl} ethan-1-amine in the active site of NarL over 10 ns simulation. Phosphorylation of NarL by small molecule phospho-donors is also investigated in the present study. Here we suggest that nitro benzene - amine piperidine moiety can be an effective lead candidate for developing novel anti-tuberculosis drugs.

Characterization of rifampicin-resistant Mycobacterium tuberculosis in Khyber Pakhtunkhwa, Pakistan

“…amplicon-based), suitable for a low resource setting. These methods are also robust to mixed infections and heteroresistance 35 , 38 , which were present in our study and likely driven by the high transmission setting. Large-scale approaches using whole genome sequencing and analysis will assist with understanding the epidemiology and risk groups or factors underpinning the transmission of TB, as well as provide insights into drug resistance and compensatory mechanisms.…”

Small Molecule Inhibitors of the Response Regulator ArsR Exhibit Bactericidal Activity against Helicobacter pylori

“…These low molecular weight ligands (known as N-binders) inhibited the activity of essential proteins by binding to and destabilizing or blocking the active site of enzymes, redox proteins, membrane transporters or transcription factors. In the case of bacterial transcriptional regulators, N-binders could inhibit or alter protein dimerization, prevent protein phosphorylation or directly block the binding to target DNA promoters by steric impediment or interaction with amino acid residues involved in the DNA binding motif structure [4,16,17,[33][34][35]. Thus, several N-binders of the H. pylori essential response regulator HsrA have previously demonstrated potent bactericidal activities against different antibiotic-resistant strains of this pathogen.…”

Progress Overview of Bacterial Two-Component Regulatory Systems as Potential Targets for Antimicrobial Chemotherapy

“…These peptides, indeed, impaired the auto-phosphorylation of the DevS protein. The NarX/NarL TCS could be another possible drug target in M. tuberculosis , for which a small inhibitor candidate, presumably targeting the NarL response regulator, was reported [ 72 ]. This compound and its properties are addressed in the following section.…”

“…Thus, Rhein may have another application as a potential TCS inhibitor. Another example of an in silico approach was the molecular docking analysis of the phosphorylation site of NarL from M. tuberculosis [ 72 ]. Using this strategy, the compound 1-{1-[(3-nitrophenyl) methyl] piperidin-2-yl} ethan-1-amine was predicted to block the phosphorylation of NarL.…”

“… WalK Dimerization [ 59 , 60 ] AIP analogues AgrC, ComD, FsrC etc. AIP sensing [ 63 , 64 , 65 , 66 , 67 , 68 , 69 ] DevR mimetic peptides DevS Auto-phosphorylation [ 71 ] Response regulator inhibitors Lactoferricin B BasR, CreB Phosphorylation [ 76 ] Rhein PhoP Phosphorylation [ 79 ] Nitrophenyl derivative NarL Phosphorylation [ 72 ] Alkyl imidazoles AlgR1 Binding to target DNAs [ 17 ] Walrycin WalR Dimerization …”