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Genomic and structural insights into the atpB L173I substitution: modulation of the F₀ rotor architecture in Mycobacterium tuberculosis ATP synthase and altered Bedaquiline binding dynamics.

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Τίτλος: Genomic and structural insights into the atpB L173I substitution: modulation of the F₀ rotor architecture in Mycobacterium tuberculosis ATP synthase and altered Bedaquiline binding dynamics.
Συγγραφείς: Thankamani A; Laboratory of Integrative Genomics, Department of Integrative Biology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India., Doss C GP; Laboratory of Integrative Genomics, Department of Integrative Biology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India. georgepriyadoss@vit.ac.in.
Πηγή: World journal of microbiology & biotechnology [World J Microbiol Biotechnol] 2026 Sep 03; Vol. 42 (9). Date of Electronic Publication: 2026 Sep 03.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Springer Country of Publication: Germany NLM ID: 9012472 Publication Model: Electronic Cited Medium: Internet ISSN: 1573-0972 (Electronic) Linking ISSN: 09593993 NLM ISO Abbreviation: World J Microbiol Biotechnol Subsets: MEDLINE
Imprint Name(s): Publication: 2005- : Berlin : Springer
Original Publication: Oxford, OX, UK : Published by Rapid Communications of Oxford Ltd in association with UNESCO and in collaboration with the International Union of Microbiological Societies, c1990-
Ιατρικοί όροι (MeSH): Diarylquinolines*/pharmacology , Diarylquinolines*/metabolism , Diarylquinolines*/chemistry , Mycobacterium tuberculosis*/genetics , Mycobacterium tuberculosis*/enzymology , Mycobacterium tuberculosis*/drug effects , Bacterial Proton-Translocating ATPases*/genetics , Bacterial Proton-Translocating ATPases*/chemistry , Bacterial Proton-Translocating ATPases*/metabolism , Mitochondrial Proton-Translocating ATPases*/genetics , Mitochondrial Proton-Translocating ATPases*/chemistry , Mitochondrial Proton-Translocating ATPases*/metabolism, Antitubercular Agents/pharmacology ; Bacterial Proteins/genetics ; Bacterial Proteins/chemistry ; Bacterial Proteins/metabolism ; Molecular Dynamics Simulation ; Mutation ; Protein Binding ; Whole Genome Sequencing ; Amino Acid Substitution ; Adenosine Triphosphate ; Binding Sites
Περίληψη: The F₀F₁ ATP synthase of Mycobacterium tuberculosis (M. tuberculosis) is an essential membrane-embedded rotary motor responsible for ATP synthesis and maintenance of the proton motive force in bacteria. The transmembrane F₀ domain comprises the c-subunit (atpE) and the a-subunit (atpB). Their coordinated interactions are needed for proton translocation and torque generation. Bedaquiline (BDQ), FDA-approved diarylquinoline for the treatment of multidrug-resistant tuberculosis (MDR-TB), targets the F₀ motor by binding at the a-c interface and inhibiting rotary catalysis. To the best of our knowledge, this study represents the first attempt to analyze the effects of mutations in the atpB protein on its structural stability in the F₀ domain, thereby highlighting the novelty of this work. In this study, we integrated Indian whole-genome sequencing (WGS) datasets (PRJNA37907) with long-timescale (1000 ns) membrane-embedded molecular dynamics (MD) simulations. Among 57 atpB mutations identified from WGS analysis, L173I was selected for structural and MD analysis. L173I is located at the atpB-atpE interface near the BDQ-binding region, despite V177L and S184A showing higher prevalence. Comparative MD simulations encompassed four systems: wild-type apo, wild-type with BDQ, L173I apo, and L173I with BDQ. Structural interrogation revealed that the L173I substitution induces subtle destabilization of the global fold of the atpB-atpE complex relative to the apo state, while more critically attenuating inter-subunit contacts between the a-subunit and the c-ring. These perturbations provide a mechanistic rationale for reduced BDQ susceptibility, arising from altered interfacial dynamics rather than complete abrogation of drug binding. This integrative genomic-structural framework advances our understanding of ATP synthase-mediated resistance in M. tuberculosis.
(© 2026. The Author(s), under exclusive licence to Springer Nature B.V.)
Competing Interests: Declarations. Ethics approval: Not appicable. Author Disclosure: Use of writing Assistance: During the preparation of this article, the author(s) used Grammarly only to improve the clarity, readability, and overall quality of the manuscript. Consent to publish: All authors have consented for publication. Concent to participate: Not applicable. Competing interests: The authors declare no competing interests.
References: Electrophoresis. 1997 Dec;18(15):2714-23. (PMID: 9504803)
Lancet Microbe. 2023 Jan;4(1):e20. (PMID: 36521512)
Ann Pharmacother. 2014 Jan;48(1):107-15. (PMID: 24259600)
J Biomol Struct Dyn. 2024;42(20):10937-10949. (PMID: 37728541)
J Infect Public Health. 2024 Jan;17(1):137-142. (PMID: 38000314)
J Infect Public Health. 2023 Dec;16(12):2058-2065. (PMID: 37948837)
RSC Med Chem. 2025 Jan 8;16(4):1476-1498. (PMID: 39790127)
J Glob Antimicrob Resist. 2020 Sep;22:308-316. (PMID: 32247079)
Antimicrob Agents Chemother. 2012 May;56(5):2326-34. (PMID: 22354303)
PLoS One. 2024 Mar 27;19(3):e0301060. (PMID: 38536792)
Indian J Community Med. 2023 May-Jun;48(3):436-442. (PMID: 37469917)
Cureus. 2022 Aug 29;14(8):e28519. (PMID: 36185922)
J Comput Chem. 2008 Aug;29(11):1859-65. (PMID: 18351591)
Nature. 2021 Jan;589(7840):143-147. (PMID: 33299175)
Clin Infect Dis. 2018 May 2;66(10):1625-1630. (PMID: 29126225)
Proc Natl Acad Sci U S A. 2021 Nov 23;118(47):. (PMID: 34782468)
Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W306-10. (PMID: 15980478)
Prog Biophys Mol Biol. 2023 Jul-Aug;180-181:87-104. (PMID: 37105260)
Contributed Indexing: Keywords: ATP-synthase; Drug resistance; Molecular Dynamic simulation; Tuberculosis
Substance Nomenclature: 0 (Diarylquinolines)
78846I289Y (bedaquiline)
0 (Antitubercular Agents)
0 (Bacterial Proteins)
EC 3.6.1.- (Bacterial Proton-Translocating ATPases)
EC 3.6.3.- (Mitochondrial Proton-Translocating ATPases)
8L70Q75FXE (Adenosine Triphosphate)
Entry Date(s): Date Created: 20260903 Date Completed: 20260903 Latest Revision: 20261008
Update Code: 20261008
DOI: 10.1007/s11274-026-05173-9
PMID: 42690482
Βάση Δεδομένων: MEDLINE
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  – Url: https://dx.doi.org/doi:10.1007/s11274-026-05173-9
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  Data: Genomic and structural insights into the atpB L173I substitution: modulation of the F₀ rotor architecture in Mycobacterium tuberculosis ATP synthase and altered Bedaquiline binding dynamics.
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  Data: The F₀F₁ ATP synthase of Mycobacterium tuberculosis (M. tuberculosis) is an essential membrane-embedded rotary motor responsible for ATP synthesis and maintenance of the proton motive force in bacteria. The transmembrane F₀ domain comprises the c-subunit (atpE) and the a-subunit (atpB). Their coordinated interactions are needed for proton translocation and torque generation. Bedaquiline (BDQ), FDA-approved diarylquinoline for the treatment of multidrug-resistant tuberculosis (MDR-TB), targets the F₀ motor by binding at the a-c interface and inhibiting rotary catalysis. To the best of our knowledge, this study represents the first attempt to analyze the effects of mutations in the atpB protein on its structural stability in the F₀ domain, thereby highlighting the novelty of this work. In this study, we integrated Indian whole-genome sequencing (WGS) datasets (PRJNA37907) with long-timescale (1000 ns) membrane-embedded molecular dynamics (MD) simulations. Among 57 atpB mutations identified from WGS analysis, L173I was selected for structural and MD analysis. L173I is located at the atpB-atpE interface near the BDQ-binding region, despite V177L and S184A showing higher prevalence. Comparative MD simulations encompassed four systems: wild-type apo, wild-type with BDQ, L173I apo, and L173I with BDQ. Structural interrogation revealed that the L173I substitution induces subtle destabilization of the global fold of the atpB-atpE complex relative to the apo state, while more critically attenuating inter-subunit contacts between the a-subunit and the c-ring. These perturbations provide a mechanistic rationale for reduced BDQ susceptibility, arising from altered interfacial dynamics rather than complete abrogation of drug binding. This integrative genomic-structural framework advances our understanding of ATP synthase-mediated resistance in M. tuberculosis.<br /> (© 2026. The Author(s), under exclusive licence to Springer Nature B.V.)
– Name: Abstract
  Label: Competing Interests
  Group: Ab
  Data: Declarations. Ethics approval: Not appicable. Author Disclosure: Use of writing Assistance: During the preparation of this article, the author(s) used Grammarly only to improve the clarity, readability, and overall quality of the manuscript. Consent to publish: All authors have consented for publication. Concent to participate: Not applicable. Competing interests: The authors declare no competing interests.
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  Label: References
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  Data: Electrophoresis. 1997 Dec;18(15):2714-23. (PMID: <searchLink fieldCode="PM" term="%229504803%22">9504803)</searchLink><br />Lancet Microbe. 2023 Jan;4(1):e20. (PMID: <searchLink fieldCode="PM" term="%2236521512%22">36521512)</searchLink><br />Ann Pharmacother. 2014 Jan;48(1):107-15. (PMID: <searchLink fieldCode="PM" term="%2224259600%22">24259600)</searchLink><br />J Biomol Struct Dyn. 2024;42(20):10937-10949. (PMID: <searchLink fieldCode="PM" term="%2237728541%22">37728541)</searchLink><br />J Infect Public Health. 2024 Jan;17(1):137-142. (PMID: <searchLink fieldCode="PM" term="%2238000314%22">38000314)</searchLink><br />J Infect Public Health. 2023 Dec;16(12):2058-2065. (PMID: <searchLink fieldCode="PM" term="%2237948837%22">37948837)</searchLink><br />RSC Med Chem. 2025 Jan 8;16(4):1476-1498. (PMID: <searchLink fieldCode="PM" term="%2239790127%22">39790127)</searchLink><br />J Glob Antimicrob Resist. 2020 Sep;22:308-316. (PMID: <searchLink fieldCode="PM" term="%2232247079%22">32247079)</searchLink><br />Antimicrob Agents Chemother. 2012 May;56(5):2326-34. (PMID: <searchLink fieldCode="PM" term="%2222354303%22">22354303)</searchLink><br />PLoS One. 2024 Mar 27;19(3):e0301060. (PMID: <searchLink fieldCode="PM" term="%2238536792%22">38536792)</searchLink><br />Indian J Community Med. 2023 May-Jun;48(3):436-442. (PMID: <searchLink fieldCode="PM" term="%2237469917%22">37469917)</searchLink><br />Cureus. 2022 Aug 29;14(8):e28519. (PMID: <searchLink fieldCode="PM" term="%2236185922%22">36185922)</searchLink><br />J Comput Chem. 2008 Aug;29(11):1859-65. (PMID: <searchLink fieldCode="PM" term="%2218351591%22">18351591)</searchLink><br />Nature. 2021 Jan;589(7840):143-147. (PMID: <searchLink fieldCode="PM" term="%2233299175%22">33299175)</searchLink><br />Clin Infect Dis. 2018 May 2;66(10):1625-1630. (PMID: <searchLink fieldCode="PM" term="%2229126225%22">29126225)</searchLink><br />Proc Natl Acad Sci U S A. 2021 Nov 23;118(47):. (PMID: <searchLink fieldCode="PM" term="%2234782468%22">34782468)</searchLink><br />Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W306-10. (PMID: <searchLink fieldCode="PM" term="%2215980478%22">15980478)</searchLink><br />Prog Biophys Mol Biol. 2023 Jul-Aug;180-181:87-104. (PMID: <searchLink fieldCode="PM" term="%2237105260%22">37105260)</searchLink>
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