Abstract
Tuberculosis is still one of the top 10 causes of deaths worldwide, especially with the emergence of multidrug-resistant tuberculosis. Rifampicin, as the most effective first-line antituberculosis drug, also develops resistance due to the mutation on Mycobacterium tuberculosis (Mtb) RNA polymerase. Among these mutations, three mutations at position 451 (H451D, H451Y, H451R) are associated with high-level resistance to rifampicin. However, the resistance mechanism of Mtb to rifampicin is still unclear. In this work, to explore the resistance mechanism of Mtb to rifampicin due to H451D/Y/R mutations, we combined the molecular dynamics simulation, molecular mechanics generalized-Born surface area calculation, dynamic network analysis, and residue interactions network analysis to compare the interaction change of rifampicin with wild-type RNA polymerase and three mutants. The results of molecular mechanics generalized-Born surface area calculations indicate that the binding free energy of rifampicin with three mutants decreases. In addition, the dynamic network analysis and residue interaction network analysis show that when H451 was mutated, the interactions of residue 451 with its adjacent residues such as Q438, F439, M440, D441, and S447 disappeared or weakened, increasing the flexibility of binding pocket. At the same time, the disappearance of hydrogen bonds between R613 and rifampicin caused by the flipping of R613 is another important reason for the reduction of binding ability of rifampicin in H451D/Y mutants. In H451R mutant, the mutation causes the binding pocket change too much so that the position of rifampicin has a large movement in the binding pocket. In this study, the resistance mechanism of rifampicin at the atomic level is proposed. The proposed drug-resistance mechanism will provide the valuable guidance for the design of antituberculosis drugs.
Highlights
Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis (Mtb), is the leading cause from a single infectious agent worldwide
molecular dynamics (MD) simulations together with MM-GBSA, dynamic network analysis, and residue interaction network (RIN) analysis were carried out on the complexes of rifampicin with the wild-type Mtb-RNAP and H451D/Y/R mutants to explore the resistant mechanism of rifampicin
The reduced binding affinity for the studied mutants mainly comes from the loss of van der Waals contribution of D441, P489, E490, N493, I497, and Q614 and electrostatic contribution of Q438, F439, and R613 in mutants
Summary
Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis (Mtb), is the leading cause from a single infectious agent worldwide. A pathogenic bacterium species of the family Mycobacteriaceae, can attack the lung of people and spread in the population through the droplets from the throat of an active TB infection patient (Mishra and Surolia, 2018). The 2018 WHO Global Tuberculosis Report (Organization, 2018) estimated 10.0 million new cases of TB and 1.6 million deaths in 2017. It spreads widely, TB is preventable and curable. The 6-month short-course regimen with a combination of four antiTB drugs (rifampicin, isoniazid, pyrazinamide, and ethambutol) has been used as a standard treatment for active, drug-susceptible TB patients over the past decades (Service and Council, 1981; Chang et al, 2018; Seid et al, 2018; Tiberi et al, 2018). The multidrug-resistant tuberculosis (MDR-TB), which at least resists to both rifampicin and isoniazid, had been emerged in the early 1990s due to multiple factors (He et al, 2008; Sandgren et al, 2009; Ahmad et al, 2018)
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