Christoffels, A. | bioRxiv Science

bioRxiv2022

Condition-Specific Mapping of Operons (COSMO) using dynamic and static genome data

An operon is a set of adjacent genes which are transcribed into a single messenger RNA. Operons allow prokaryotes to efficiently circumvent environmental stresses. It is estimated that about 60% of the Mycobacterium tuberculosis genome is arranged into operons, which makes them interesting drug targets in the face of emerging drug resistance. We therefore developed COSMO - a tool for operon prediction in M. tuberculosis using RNA-seq data. We analyzed four algorithmic parameters and benchmarked COSMO against two top performing operon predictors. COSMO outperformed both predictors in its accuracy and in its ability to distinguish operons activated under distinct conditions. Author SummaryOperons may be important drug targets for the development of effective anti-microbials to combat the emerging, global drug resistance challenge. However, there is a shortage of known Mycobacterium tuberculosis (Mtb) operons. This is exacerbated by the fact that current operon predictors are not optimized for the unique genome of Mtb. COSMO removes the limitations imposed by using the constraints of a specific organisms genome and exploits RNA-seq data instead. This allows COSMO to more accurately predict full-length operons in Mtb, and it also avails COSMO to other microorganisms for the same purpose.

bioinformatics↗

bioRxiv2020

Repurposing Novobiocin for activity against latency associated Mycobacterium tuberculosis drug target nicotinate-nucleotide adenylyltransferase (Rv2421c)

Nicotinamide-nucleotide adenylyl transferase (Rv2421c) was selected as a potential drug target, because it has been shown, in vitro, to be essential for Mycobacterium tuberculosis growth. It is conserved between mycobacterium species, is up-regulated during dormancy, has a known 3D crystal structure and has no known human homologs. A model of Rv2421c in complex with nicotinic acid adenine dinucleotide and magnesium ion was constructed and subject to virtual ligand screening against the Prestwick Chemical Library and the ZINC database, which yielded 155 potential hit molecules. 3D-QSAR studies of the 155 drug molecules indicated five compounds with similar inhibitory efficiencies compared to known inhibitors of Rv2421c. Molecular docking validation and molecular dynamics simulation analysis of the top five compounds indicated that the identified inhibitor molecules bind to Rv2421c with comparable efficiency as the substrate DND. Subsequent in vitro testing of the five compounds identified Novobiocin sodium salt with activity against Mycobacterium tuberculosis at 50 M, 25M and weakly at 10M concentrations. Although, Novobiocin salt targets Mycobacterium tuberculosis DNA gyrase B our studies suggest that it has the potential to be repurposed to inhibit Rv2421c. Subsequent in silico structural analysis of known Novobiocin sodium salt derivatives against Rv2421c suggest promising alternatives for the treatment of Mycobacterium tuberculosis. Author SummaryRv2421c has been shown to be essential for Mycobacterium tuberculosis growth, shares no homology to known proteins in the human host, is conserved between various Mycobacterium species, is up-regulated during the non-replicative metabolic growth phase, making it an attractive drug target. It has a known 3D structure which has been exploited to screen for putative compounds within the Prestwick chemical library and ZINC database, resulting in the successful identification of 155 candidate compounds. Thereafter 3D-QSAR, molecular docking and molecular dynamics simulation studies were used to prioritize five potential compounds. Of the five compounds tested in vitro, only one, a Novobiocin disodium salt, showed activity against Mycobacterium tuberculosis at 50, 25 and weakly at 10 M concentrations. Novobiocin is known to target Mycobacterium tuberculosis DNA gyrase B, but emerging resistance stimulated us to seek derivatives to target Rv2421c as alternatives for the treatment of Mycobacterium tuberculosis. Docking studies supported the higher binding affinities of Novobiocin derivatives to Rv2421c compared to DNA gyrase B. Future studies will involve testing these Novobiocin derivatives for activity against Mycobacterium tuberculosis.

bioinformatics↗