Abstract
In the current era of a pandemic, infections of COVID-19 and Tuberculosis (TB) enhance the detrimental effects of both diseases in suffering individuals. The resistance mechanisms evolving in Mycobacterium tuberculosis are limiting the efficiency of current therapeutic measures and pressurizing the stressed medical infrastructures. The bacterial efflux pumps enable the development of resistance against recently approved drugs such as bedaquiline and clofazimine. Consequently, the MmpS5-MmpL5 protein system was selected because of its role in efflux pumping of anti-TB drugs. The MmpS5-MmpL5 systems of Mycobacterium smegmatis were modelled and the virtual screening was performed using an ASINEX library of 5968 anti-bacterial compounds. The inhibitors with the highest binding affinities and QSAR based highest predicted inhibitory concentration were selected. The MmpS5-MmpL5 associated systems with BDE_26593610 and BDD_27860195 showed highest inhibitory parameters. These were subjected to 100 ns Molecular Dynamics simulations and provided the validation regarding the interaction studies. The in vitro studies demonstrated that the BDE_26593610 and BDD_27860195 can be considered as active inhibitors for M. smegmatis MmpS5-MmpL5. The outcomes of this study can be utilized in other experimentation aimed at drug design and discovery against the drug resistance strains of M. tuberculosis.
Highlights
The predicted model showed the confidence level of 100% and on the stereo-chemical validation using the Ramachandran plot showed 98.3% of the residues were occupied in the allowed regions
The active efflux systems in the Mycobacterium species are among the major causes leading to the development of multi-drug resistance conditions and their low concentration activities are associated with the generation of drug tolerant mutations
A shift is needed for the development of inhibitors targeting bacteria efflux systems
Summary
The increasing evolution of drug resistance during tuberculosis (TB) infection has made it a global challenge [1,2]. The multidrug and extensive drug-resistance strains (MDR- and XDR-TB) of Mycobacterium tuberculosis resulted in reduced efficiency of available treatment [3], which makes it necessary to formulate new potent drug molecules [4,5]. In combination with TB, the illnesses associated with the COVID-19 pandemic are usually manifested in the respiratory systems and the severity result in system failures [6]. In combination with the COVID-19 global occurrence, the other epidemics are propagating in a parallel manner and it is imperative not to forget the conditions
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