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BioSystems 209 (2021) 104509

Study of the bioenergetics to identify the novel pathways as a drug target Image against Mycobacterium tuberculosis using Petri net

Sakshi Gupta a, Zeeshan Fatima b,∗, Sunita Kumawat a,∗

a Department of Mathematics, Amity School of Applied Sciences, Amity University Haryana, Gurugram, India
b Amity Institute of Biotechnology, Amity University Haryana, Gurugram, India


Petri nets Antimycobacterials Bioenergetics Mycobacterium tuberculosis P-invariant


Tuberculosis is one of the life-threatening diseases globally, caused by the bacteria Mycobacterium tuberculosis. In order to control this epidemic globally, there is an urgent need to discover new drugs with novel mechanism of action that can help in shortening the duration of treatment for both drug resistant and drug sensitive tuberculosis. Mycobacterium essentially depends on oxidative phosphorylation for its growth and establishment of pathogenesis. This pathway is unique in Mycobacterium tuberculosis as compared to host due to the differences in some of the enzyme complexes carrying electron transfer. Hence, it serves as an important drug target area. The uncouplers which inhibit adenosine triphosphate synthesis, could play a vital role in serving as antimycobacterial agents and thus could help in eradicating this deadly disease. In this article, the bioenergetics of Mycobacterium tuberculosis are studied with and without uncouplers using Petri net. Petri net is among the most widely used mathematical and computational tools to model and study the complex biochemical networks. We first represented the bioenergetic pathway as a Petri net which is then validated and analyzed using invariant analysis techniques of Petri net. The valid mathematical models presented here are capable to explain the molecular mechanism of uncouplers and the processes occurring within the electron transport chain of Mycobacterium tuberculosis. The results explained the net behavior in agreement with the biological results and also suggested some possible processes and pathways to be studied as a drug target for developing antimycobacterials.

1. Introduction
Tuberculosis (TB), a communicable disease, is one of the major global concern related to epidemiology. About 1∕4th of the world’s population is suffering from this disease (WHO, 2020). In 1882, Robert Koch, a German microbiologist, declares that the Mycobacterium tuber- culosis (Mtb) is the cause of TB (Fogel, 2015). It is an air borne disease that spreads through coughing or sneezing of infected individuals. World Health Organization (WHO) reported that approximately 10 million people got affected with TB in 2019, among whom 1.4 million people died (WHO, 2020). First line treatment of TB involves the use of current four drug anti-TB medicines for at least six months. Such a long duration of treatment has resulted in the evolution of multi-drug resistance (MDR) and extensively-drug resistance (XDR) for TB (Black et al., 2014). To cure MDR TB, second line drug treatment with 4 to 6 anti-TB medicines for up to two years is required, which has severe side effects and economic burden on TB patients. However, in patients developing XDR TB, the second line drug treatment often becomes ineffective, leaving them without further treatment possibilities (Bald
et al., 2017). The research has been conducted to get insights to spread- ing, diagnosis and treatment of TB (Torfs et al., 2019). Considering its severity, there is a global need to discover novel drug targets that can efficiently reduce the duration of treatment and target MDR TB and XDR TB strains, hence help in eradicating this life-threatening disease. Oxidative phosphorylation is a bioenergetic pathway generating adenosine triphosphate (ATP) from the phosphorylation of adenosine diphosphate (ADP). In oxidative phosphorylation, a proton motive force (pmf) is established by the enzyme complexes of electron transport chain (ETC) and subsequently ATP synthase maneuvers this pmf to produce ATP from ADP and inorganic phosphate (