RV1258C EFFLUX PUMP (TAP) IN MYCOBACTERIUM TUBERCULOSIS – REVIEW ABOUT MUTATIONS AND INHIBITION MECHANISM

Conrado Pizzolatto Castanho; Adriano Werhli; Karina Machado

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Submission

Paper Title

RV1258C EFFLUX PUMP (TAP) IN MYCOBACTERIUM TUBERCULOSIS – REVIEW ABOUT MUTATIONS AND INHIBITION MECHANISM

Authors

Conrado Pizzolatto Castanho
Adriano Werhli
Karina Machado

Modality

Xpress presentation

Subject area

Structural Bioinformatics

Publishing Date

26/04/2022

Country of Publishing

Brasil

Language of Publishing

Inglês

Paper Page

https://www.even3.com.br/anais/xmeetingxp2021/420610-rv1258c-efflux-pump-(tap)-in-mycobacterium-tuberculosis--review-about-mutations-and-inhibition-mechanism

ISBN

978-65-5941-645-5

Keywords

Efflux pump, Rv1258c (TAP), Tuberculosis.

Summary

The efflux pump was first documented in 1980 and emerged as a potential mechanism of drug resistance. Mycobacterium tuberculosis (Mtb) has one of the largest number of efflux pumps compared to the size of its genome. From these efflux pumps, one important is Rv1258c (TAP), from the Major Facilitator Superfamily (MFS). This efflux pump TAP contributes to the Mtb intrinsic resistance to antibiotics using the electrochemical gradient as an energy source. Furthermore, it promotes the efflux of substrates through three different mechanisms: uniport, simport or antiport, which can lead to the transport of multiple molecules. Thus, in this work we performed a review of the literature about the mechanism of mutation and inhibition of the RV1258c efflux pump (TAP) using Pubmed, Lilacs and Scielo. As a result of our review, we can highlight that overexpression this transporter TAP, mainly caused by the subinhibitory presence of antibiotics, can promote the accumulation of mutations in the target gene (Rv1258c) contributing to the development of the multiresistant phenotypes, providing a significant change in the spectrum of substrates. Furthermore, we found a relevant study describing single point mutations in the Rv1258c gene: V219A and S292L. These mutations are related to significant resistance to pyrazinamide, isoniazid and streptomycin where. V219A resulted in a low level of drug resistance, while the S292L mutation caused a higher level of resistance. To minimize the strong resistance mechanism of the efflux pump in Mtb, some studies have shown the importance of efflux pump inhibition, showing that cell energy reduction or direct connection with efflux pumps can serve as alternatives to achieve inhibition, leading to the understanding that the molecular structure and physicochemical properties of the efflux pump must be taken into account to accurately predict new substrates that can act as inhibitors. In this context, the most studied inhibitors are ion channel blockers such as the phenothiazines thioridazine and chlorpromazine, phenylalkylamines verapamil and piperine, which was effective in inhibiting the transporter Rv1258c and resistance to isoniazid and pyrazinamide in the S292L mutant. This inhibition of efflux activity becomes a promising approach to combat bacterial resistance. Therefore, this review showed the importance of searching for mutations in the efflux pump Rv1258c (TAP) as well as alternatives for dealing with this mechanism for instance the development and usage of inhibitors, aiming to improve the development of strategies that can contribute with the effective treatment of the disease. Thus as a result we are going to model these mutations using Alphafold and evaluate their interaction through molecular docking simulations with phenothiazines and phenylalkylamines.

Title of the Event: X-Meeting XPerience 2021
Title of the Proceedings of the event: X-Meeting presentations
Name of the Publisher: Even3
Means of Dissemination: Meio Digital

How to cite

CASTANHO, Conrado Pizzolatto; WERHLI, Adriano; MACHADO, Karina. RV1258C EFFLUX PUMP (TAP) IN MYCOBACTERIUM TUBERCULOSIS – REVIEW ABOUT MUTATIONS AND INHIBITION MECHANISM.. In: X-Meeting presentations. Anais...São Paulo(SP) AB3C, 2021. Available in: https//www.even3.com.br/anais/xmeetingxp2021/420610-RV1258C-EFFLUX-PUMP-(TAP)-IN-MYCOBACTERIUM-TUBERCULOSIS--REVIEW-ABOUT-MUTATIONS-AND-INHIBITION-MECHANISM. Access in: 16/07/2025