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S288T mutation altering MmpL3 periplasmic domain channel and H-bond network: a novel dual drug resistance mechanism

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Abstract

Context

Mycobacterial membrane proteins Large 3 (MmpL3) is responsible for the transport of mycobacterial acids out of cell membrane to form cell wall, which is essential for the survival of Mycobacterium tuberculosis (Mtb) and has become a potent anti-tuberculosis target. SQ109 is an ethambutol (EMB) analogue, as a novel anti-tuberculosis drug, can effectively inhibit MmpL3, and has completed phase 2b-3 clinical trials. Drug resistance has always been the bottleneck problem in clinical treatment of tuberculosis. The S288T mutant of MmpL3 shows significant resistance to the inhibitor SQ109, while the specific action mechanism remains unclear. The results show that MmpL3 S288T mutation causes local conformational change with little effect on the global structure. With MmpL3 bound by SQ109 inhibitor, the distance between D710 and R715 increases resulting in H-bond destruction, but their interactions and proton transfer function are still restored. In addition, the rotation of Y44 in the S288T mutant leads to an obvious bend in the periplasmic domain channel and an increased number of contact residues, reducing substrate transport efficiency. This work not only provides a possible dual drug resistance mechanism of MmpL3 S288T mutant but also aids the development of novel anti-tuberculosis inhibitors.

Methods

In this work, molecular dynamics (MD) and quantum mechanics (QM) simulations both were performed to compare inhibitor (i.e., SQ109) recognition, motion characteristics, and H-bond energy change of MmpL3 after S288T mutation. In addition, the WT_SQ109 complex structure was obtained by molecular docking program (Autodock 4.2); Molecular Mechanics/ Poisson Boltzmann Surface Area (MM-PBSA) and Solvated Interaction Energy (SIE) methods were used to calculate the binding free energies (∆Gbind); Geometric criteria were used to analyze the changes of hydrogen bond networks.

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Data availability

All data generated or analyzed during this study are included in this published article.

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Funding

This work was supported by the Research and Development Plan in Key Areas of Guangdong Province (2022B1111050003).

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Author notes

  1. Yutong Ge, Qing Luo, and Ling Liu contributed equally to this work.

Authors and Affiliations

  1. Department of Thoracic Oncology, Affiliated Cancer Hospital, Guizhou Medical University, Guiyang, China

    Yutong Ge, Zhigang Zhang & Weiwei Ouyang

  2. Key Laboratory of Medicinal and Edible Plants Resources Development of Sichuan Education Department, School of Pharmacy, Chengdu University, Chengdu, 610106, China

    Yutong Ge, Ling Liu, Quanshan Shi, Xinru Yue, Lingkai Tang, Li Liang & Jianping Hu

  3. Faculty of Applied Sciences, Macao Polytechnic University, Macao, 999078, China

    Qing Luo

Authors
  1. Yutong Ge
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  2. Qing Luo
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  3. Ling Liu
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  4. Quanshan Shi
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  8. Li Liang
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Contributions

YG: resources, writing original draft. QL: conceptualization, resources. LL: review, editing. QS: visualization. ZZ: data mining. XY and LT: project administration, supervision. LL: project administration, supervision, methodology. JH and WO: funding acquisition.

Corresponding authors

Correspondence to Jianping Hu or Weiwei Ouyang.

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Key messages

• The initial structure used for subsequent MD simulations is provided and verified through homology modeling and rational mutation.

• The convergence trajectories of four systems (WT_apo, S288T_apo, WT_SQ109, and S288T_SQ109) are obtained by all-atom comparison MD simulations.

• A series of molecular simulation strategies were adopted to deeply understand the structural and hydrogen bond network changes caused by S288T mutation in Mtb MmpL3 and then to provide possible drug resistance against SQ109.

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Ge, Y., Luo, Q., Liu, L. et al. S288T mutation altering MmpL3 periplasmic domain channel and H-bond network: a novel dual drug resistance mechanism. J Mol Model 30, 39 (2024). https://doi.org/10.1007/s00894-023-05814-y

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