In Silico Approach for Phytocompound-Based Drug Designing to Fight Efflux Pump-Mediated Multidrug-Resistant Mycobacterium tuberculosis

Abstract

Tuberculosis (TB), caused by the bacteria Mycobacterium tuberculosis , is one of the principal causes of death in the world despite the existence of a significant number of antibiotics aimed against it. This is mainly due to the drug resistance mechanisms present in the bacterium, which leads to multidrug-resistant tuberculosis (MDR-TB). Additionally, the development of new antibiotics has become limited over the years. Although there are various drug resistance mechanisms present, efflux pumps are of utmost importance because they extrude out several dissimilar antitubercular drugs out of the cell. There are many efflux pump proteins present in Mycobacterium tuberculosis . Therefore, blocking these efflux pumps by inhibitors can raise the efficacy of the existing antibiotics and may also pave the path for the discovery and synthesis of new drugs. Plant compounds can act as a resource for the development of efflux pump inhibitors (EPIs), which may eventually replace or augment the current therapeutic options. This is mainly because plants have been traditionally used for ages for food or treatment and are considered safe with little or no side effects. Various computational tools are available which are used for the virtual screening of a large number of phytocompounds within a short span of time. This review aims to highlight the mechanism and appearance of drug resistance in Mycobacterium tuberculosis with emphasis on efflux pumps along with the significance of phytochemicals as inhibitors of these pumps and their screening strategy by computational approaches.

Clove Buds Volatile Compounds: Inhibitory Activity on Mycobacterium Growth and Molecular Docking on Mmr Efflux Pump Drug Resistance

“…[29] It has been reported that the deletion of lfrA and Mmr homologue rendered the strains more susceptible to EtBr and fluoroquinolones among others. [29] Verapamil (VER) is an EP inhibitor that has also been shown to potentiate the effect of bedaquiline on Mycobacterium tuberculosis. [30] Concerning plant-based efflux pump inhibitors, certain alkaloids have been proven effective, as the case of reserpine (RES) which is an antagonist of the P-gp EP, that may completely reverse the drug efflux in multidrug resistant bacteria.…”

“…Several efflux transporters are involved in drug resistance of mycobacteria [25,28] . Mmr (rv3065) is an EP belonging to small multidrug resistance (SMR) family conferring resistance to many antimicrobial agents such as ethidium bromide (EtBr) and erythromycin [29] . It has been reported that the deletion of lfrA and Mmr homologue rendered the strains more susceptible to EtBr and fluoroquinolones among others [29] .…”

“…Verapamil (VER) is an EP inhibitor that has also been shown to potentiate the effect of bedaquiline on Mycobacterium tuberculosis [30] . Concerning plant‐based efflux pump inhibitors, certain alkaloids have been proven effective, as the case of reserpine (RES) which is an antagonist of the P‐gp EP, that may completely reverse the drug efflux in multidrug resistant bacteria [29] . In the best of our knowledge, scarcely are studies that had been focused on the evaluation of the potential action of clove chemicals against the multidrug resistance caused by EP systems.…”

“…[25,28] Mmr (rv3065) is an EP belonging to small multidrug resistance (SMR) family conferring resistance to many antimicrobial agents such as ethidium bromide (EtBr) and erythromycin. [29] It has been reported that the deletion of lfrA and Mmr homologue rendered the strains more susceptible to EtBr and fluoroquinolones among others. [29] Verapamil (VER) is an EP inhibitor that has also been shown to potentiate the effect of bedaquiline on Mycobacterium tuberculosis.…”

Novel Approaches for the Treatment of Drug-Resistant Tuberculosis

“…[3] It is caused by the Mycobacterium tuberculosis (Mtb) bacteria, belonging to the family Mycobacteriaceae, discovered by Robert Koch in 1882. It is a non-motile aerobic bacillus [4] that causes pulmonary infection when an infected person, during coughing or sneezing, releases the droplets with droplet nuclei of 1-5 microns containing viable Mtb, and these droplets are inhaled and reach the respiratory alveolar units. [5] With the phagocytic efforts of the host's innate immune cells which includes primarily alveolar macrophages, dendritic cells, monocytes, and neutrophils, Mtb is still able to persist in the host and results in the formation of granulomas.…”