Abstract
Tuberculosis is an highly contagious disease still considered by the WHO as one of most infectious diseases worldwide. The therapeutic approach, used to prevent and treat tuberculosis targets the Mycobacterium tuberculosis complex, comprises a combination of drugs administrated for long periods of time, which, in many cases, could cause several adverse effects and, consequently, low compliance of the patient to the treatment and drug-resistance. Therefore, therapeutic liquid mixtures formulated with anti-tuberculosis drugs and/or adjuvants in tuberculosis therapy are an interesting approach to prevent toxic effects and resistance to anti-tuberculosis drugs. The herein formulated therapeutic liquid mixtures, including ethambutol, arginine, citric acid and water under different molar ratios, were studied through a molecular dynamics approach to understand how ethambutol and arginine could be stabilized by the presence of citric acid and/or water in the mixture. To gain insights on how the uptake of these mixtures into the mycobacteria cell may occur and how a mycobacterial ABC transporter could contribute to this transport, multiple simultaneous ligand docking was performed. Interactions between citric acid and ethambutol involving the carboxyl and hydroxyl groups of citric acid with the amines of ethambutol were identified as the most critical ones. Water molecules present in the mixture provides the necessary network of hydrogen bonds that stabilize the mixture. Molecular docking additionally provided an interesting hypothesis on how the different mixture components may favor binding of ethambutol to an ABC importer. The data presented in this work helps to better understand these mixtures as well as to provide cues on the mechanisms that allow them to cross the mycobacterial cell membrane.
Highlights
Tuberculosis persists as one of the major causes of morbidity and mortality caused by an infection, worldwide
Molecular dynamics is an unique tool that allows probing the internal structure of these therapeutic liquid mixtures and to gain insights on the interactions and configurations of each component at its molecular level (Kumari et al, 2018; Cao et al, 2019; Gutiérrez et al, 2019; Sapir and Harries, 2020)
We employed molecular dynamics (MD) simulations to study the molecular structure of each mixture, in order to gain insights on which chemical groups are involved in the formation of the eutectic mixture and to identify suitable chemical modifications that can further improve the properties of ethambutol, enabling them to be used as therapeutic delivery systems (Santos et al, 2018)
Summary
Tuberculosis persists as one of the major causes of morbidity and mortality caused by an infection, worldwide. It is an infectious disease triggered by Mycobacterium tuberculosis complex that is pathogenic in humans and animals and belongs to a group of bacteria named Mycobacteria. This group of bacteria are frequently resistant to several antibiotics, mostly due to slow absorption of the drugs through the highly hydrophobic mycobacterial cell envelope (Viveiros et al, 2003). One of the major problems in tuberculosis treatment is the emergence of multidrug resistance (MDR) that can occur during the therapy due to chromosomal mutations mechanisms (e.g., single nucleotide polymorphisms), drug-drug interactions, malabsorption of drugs and prolonged administration of multiple drugs, which in turn leads to a low compliance of the patient to the treatment (Forbes et al, 2018; Hameed et al, 2018)
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