Integrative genomic study identifies two new potential drug targets in Mycobacterium tuberculosis

The World Health Organization reports indicate that tuberculosis continues to be one of the major causes of mortality worldwide. The eradication of the disease has become challenging due to the emergence of various drug-resistant strains of Mycobacterium tuberculosis.

In a recent study published in Scientific Reports, researchers used existing whole genome sequences of M. tuberculosis and conducted a pangenomic analysis to identify potential drug targets.

​​​​​​​Study: Exploring optimal drug targets through subtractive proteomics analysis and pangenomic insights for tailored drug design in tuberculosis. Image Credit: Helena Nechaeva/Shutterstock.com​​​​​​​Study: Exploring optimal drug targets through subtractive proteomics analysis and pangenomic insights for tailored drug design in tuberculosis. Image Credit: Helena Nechaeva/Shutterstock.com

Background

Tuberculosis is considered the next most severe infectious disease after coronavirus disease 2019 (COVID-19) and is responsible for a significant percentage of the global mortality rates. It is an added cause for concern among individuals infected with human immunodeficiency virus (HIV).

The annual mortality due to tuberculosis is estimated to be around 1.6 million, among which over 180,000 are believed to be those with HIV. Furthermore, these estimates also indicate that tuberculosis-related mortality is on the rise since 2017.

Mycobacterium tuberculosis is an airborne bacterium that can disrupt the human immune system by invading macrophages, compromising the immunity of the host, and resulting in chronic infection.

Mutations in the bacterial genes that confer M. tuberculosis with extensive and multi-drug resistance and the emergence of these drug-resistant strains as the dominant variants have magnified the challenge of tuberculosis management and control, as the efficacies of antibiotics such as rifampicin and isoniazid have reduced significantly.

About the study

The present study used an integrative genomics approach to identify potential new drug targets against M. tuberculosis. They analyzed multiple existing whole genome datasets of M. tuberculosis and used subtractive proteomics and computer-aided drug discovery.

They also employed molecular docking analysis to investigate the structural interactions between the potential drug targets and existing drugs approved by the United States (U.S.) Food and Drug Administration (FDA).

The pangenome approach has been applied to identify the core genome or the set of genes that are consistently present and expressed in all the strains of the pathogen. These genes will provide a target for broad-spectrum drugs that can be used against multiple strains.

Furthermore, the development of in silico drug screening has accelerated the drug development process by selecting only relevant compounds to refine and enhance.

The pangenome analysis for all existing M. tuberculosis genomes was conducted using the bacterial pan-genome analysis tool, which identified the core and pan proteomes.

The analysis to identify potential drug targets focused only on protein sequences linked to the core genome.

The core proteome was then screened for factors such as virulence and non-homology to identify potential drug targets. Furthermore, to minimize adverse effects, the process had to ensure that these identified drug targets were dissimilar from human proteins.

Physiochemical properties of the proteins such as the isoelectric point, molecular weight, grand average of hydropathicity value, and aliphatic and instability indices were then used to further refine the proteins.

The binding affinity and fit quality were also assessed during the molecular docking analysis to evaluate the drug's effectiveness. Additionally, simulations of molecular dynamics were performed to understand the stability and behavior of the protein-ligand complex.

Major findings

The study found various therapeutic targets in the M. tuberculosis genome that could be targeted by existing FDA-approved drugs.

Extensive analyses of the physiochemical properties identified 38 proteins, of which six were determined through comparative pathway analyses to play essential roles in the bacteria's metabolic pathways.

Proteins involved in more than three metabolic pathways were identified as potential drug targets, including pantothenate synthetase and isocitrate lyase. Both enzymes are vital in the metabolic processes of M. tuberculosis.

Isocitrate lyase is involved in the glyoxylate cycle, where it helps convert isocitrate to glyoxylate and succinic acid. Furthermore, mammals lack this enzyme, making it a suitable drug target. The FDA-approved drug dihydroergotamine showed a high binding affinity for isocitrate lyase.

Pantothenate synthetase catalyzes the biosynthesis of pantothenate. Studies have shown that inhibiting pantothenate biosynthesis using pyrazinamide was effective in inhibiting M. tuberculosis growth until mutations in the panD gene coding for aspartate decarboxylase provided the bacteria with pyrazinamide resistance.

However, existing FDA-approved drugs such as abiraterone acetate or Zytiga can bind strongly to pantothenate synthetase.

Conclusions

To summarize, the study used existing genomes of M. tuberculosis and conducted an integrative genomic analysis and molecular docking simulations to identify proteins that could potentially be targeted by FDA-approved drugs to control tuberculosis.

The findings indicated that two enzymes, pantothenate synthetase and isocitrate lyase, were potential and promising drug targets based on high binding affinity with existing drugs and the low probability of adverse effects.

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