Bioenergetic reprogramming of macrophages reduces drug tolerance in Mycobacterium tuberculosis
Effective clearance of Mycobacterium tuberculosis (Mtb) requires targeting drug-tolerant populations within host macrophages. Here, we show that macrophage metabolic states govern redox heterogeneity and drug response in intracellular Mtb. Using a redox-sensitive fluorescent reporter (Mrx1-roGFP2),...
Gespeichert in:
| Hauptverfasser: | , , , , , , , , , , , , , |
|---|---|
| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
23 October 2025
|
| In: |
Nature Communications
Year: 2025, Jahrgang: 16, Pages: 1-20 |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-025-64407-w |
| Online-Zugang: | Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41467-025-64407-w Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41467-025-64407-w 
|
| Verfasserangaben: | Vikas Yadav, Sarthak Sahoo, Nitish Malhotra, Richa Mishra, Sreesa Sreedharan, Raju S. Rajmani, Siva Shanmugam, Radha K. Shandil, Shridhar Narayanan, Vivek V. Thacker, Sunil Laxman, Mohit Kumar Jolly, Aswin Sai Narain Seshasayee & Amit Singh |
MARC
| LEADER | 00000naa a2200000 c 4500 | ||
|---|---|---|---|
| 001 | 1945015411 | ||
| 003 | DE-627 | ||
| 005 | 20251208112823.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 251208s2025 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1038/s41467-025-64407-w |2 doi | |
| 035 | |a (DE-627)1945015411 | ||
| 035 | |a (DE-599)KXP1945015411 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rda | ||
| 041 | |a eng | ||
| 084 | |a 32 |2 sdnb | ||
| 100 | 1 | |a Yadav, Vikas |e VerfasserIn |0 (DE-588)1383728151 |0 (DE-627)1945017910 |4 aut | |
| 245 | 1 | 0 | |a Bioenergetic reprogramming of macrophages reduces drug tolerance in Mycobacterium tuberculosis |c Vikas Yadav, Sarthak Sahoo, Nitish Malhotra, Richa Mishra, Sreesa Sreedharan, Raju S. Rajmani, Siva Shanmugam, Radha K. Shandil, Shridhar Narayanan, Vivek V. Thacker, Sunil Laxman, Mohit Kumar Jolly, Aswin Sai Narain Seshasayee & Amit Singh |
| 264 | 1 | |c 23 October 2025 | |
| 300 | |b Illustrationen | ||
| 300 | |a 20 | ||
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Online veröffentlicht: 23. Oktober 2025 | ||
| 500 | |a Gesehen am 08.12.2025 | ||
| 520 | |a Effective clearance of Mycobacterium tuberculosis (Mtb) requires targeting drug-tolerant populations within host macrophages. Here, we show that macrophage metabolic states govern redox heterogeneity and drug response in intracellular Mtb. Using a redox-sensitive fluorescent reporter (Mrx1-roGFP2), flow cytometry, and transcriptomics, we found that macrophages with high oxidative phosphorylation (OXPHOS) and low glycolysis harbor reductive, drug-tolerant Mtb, whereas glycolytically active macrophages generate mitochondrial ROS via reverse electron transport, imposing oxidative stress on Mtb and enhancing drug efficacy. Computational and genetic analyses identified NRF2 as a key regulator linking host metabolism to bacterial redox state and drug tolerance. Pharmacological reprogramming of macrophages with the FDA-approved drug meclizine (MEC) shifted metabolism towards glycolysis, suppressed redox heterogeneity, and reduced Mtb drug tolerance in macrophages and mice. MEC exhibited no adverse interactions with frontline anti-TB drugs. These findings demonstrate the therapeutic potential of host metabolic reprogramming to overcome Mtb drug tolerance. | ||
| 650 | 4 | |a Infection | |
| 650 | 4 | |a Pathogens | |
| 650 | 4 | |a Tuberculosis | |
| 700 | 1 | |a Sahoo, Sarthak |e VerfasserIn |4 aut | |
| 700 | 1 | |a Malhotra, Nitish |e VerfasserIn |4 aut | |
| 700 | 1 | |a Mishra, Richa |e VerfasserIn |0 (DE-588)1310030189 |0 (DE-627)1870436709 |4 aut | |
| 700 | 1 | |a Sreedharan, Sreesa |e VerfasserIn |4 aut | |
| 700 | 1 | |a Rajmani, Raju S. |e VerfasserIn |4 aut | |
| 700 | 1 | |a Shanmugam, Siva |e VerfasserIn |4 aut | |
| 700 | 1 | |a Shandil, Radha K. |e VerfasserIn |4 aut | |
| 700 | 1 | |a Narayanan, Shridhar |e VerfasserIn |4 aut | |
| 700 | 1 | |a Thacker, Vivek Vijay |e VerfasserIn |0 (DE-588)1310030324 |0 (DE-627)187043692X |4 aut | |
| 700 | 1 | |a Laxman, Sunil |e VerfasserIn |4 aut | |
| 700 | 1 | |a Jolly, Mohit Kumar |e VerfasserIn |4 aut | |
| 700 | 1 | |a Seshasayee, Aswin Sai Narain |e VerfasserIn |4 aut | |
| 700 | 1 | |a Singh, Amit |e VerfasserIn |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Nature Communications |d [London] : Springer Nature, 2010 |g 16(2025), Artikel-ID 9370, Seite 1-20 |h Online-Ressource |w (DE-627)626457688 |w (DE-600)2553671-0 |w (DE-576)331555905 |x 2041-1723 |7 nnas |a Bioenergetic reprogramming of macrophages reduces drug tolerance in Mycobacterium tuberculosis |
| 773 | 1 | 8 | |g volume:16 |g year:2025 |g elocationid:9370 |g pages:1-20 |g extent:20 |a Bioenergetic reprogramming of macrophages reduces drug tolerance in Mycobacterium tuberculosis |
| 856 | 4 | 0 | |u https://doi.org/10.1038/s41467-025-64407-w |x Verlag |x Resolving-System |z kostenfrei |3 Volltext |7 0 |
| 856 | 4 | 0 | |u https://www.nature.com/articles/s41467-025-64407-w |x Verlag |z kostenfrei |3 Volltext |7 0 |
| 951 | |a AR | ||
| 992 | |a 20251208 | ||
| 993 | |a Article | ||
| 994 | |a 2025 | ||
| 998 | |g 1310030324 |a Thacker, Vivek Vijay |m 1310030324:Thacker, Vivek Vijay |d 910000 |d 911700 |e 910000PT1310030324 |e 911700PT1310030324 |k 0/910000/ |k 1/910000/911700/ |p 10 | ||
| 998 | |g 1310030189 |a Mishra, Richa |m 1310030189:Mishra, Richa |d 910000 |d 911700 |e 910000PM1310030189 |e 911700PM1310030189 |k 0/910000/ |k 1/910000/911700/ |p 4 | ||
| 999 | |a KXP-PPN1945015411 |e 4824326362 | ||
| BIB | |a Y | ||
| SER | |a journal | ||
| JSO | |a {"person":[{"role":"aut","display":"Yadav, Vikas","roleDisplay":"VerfasserIn","given":"Vikas","family":"Yadav"},{"role":"aut","display":"Sahoo, Sarthak","roleDisplay":"VerfasserIn","given":"Sarthak","family":"Sahoo"},{"given":"Nitish","family":"Malhotra","role":"aut","display":"Malhotra, Nitish","roleDisplay":"VerfasserIn"},{"family":"Mishra","given":"Richa","display":"Mishra, Richa","roleDisplay":"VerfasserIn","role":"aut"},{"role":"aut","display":"Sreedharan, Sreesa","roleDisplay":"VerfasserIn","given":"Sreesa","family":"Sreedharan"},{"given":"Raju S.","family":"Rajmani","role":"aut","display":"Rajmani, Raju S.","roleDisplay":"VerfasserIn"},{"display":"Shanmugam, Siva","roleDisplay":"VerfasserIn","role":"aut","family":"Shanmugam","given":"Siva"},{"family":"Shandil","given":"Radha K.","display":"Shandil, Radha K.","roleDisplay":"VerfasserIn","role":"aut"},{"roleDisplay":"VerfasserIn","display":"Narayanan, Shridhar","role":"aut","family":"Narayanan","given":"Shridhar"},{"display":"Thacker, Vivek Vijay","roleDisplay":"VerfasserIn","role":"aut","family":"Thacker","given":"Vivek Vijay"},{"given":"Sunil","family":"Laxman","role":"aut","roleDisplay":"VerfasserIn","display":"Laxman, Sunil"},{"family":"Jolly","given":"Mohit Kumar","display":"Jolly, Mohit Kumar","roleDisplay":"VerfasserIn","role":"aut"},{"role":"aut","roleDisplay":"VerfasserIn","display":"Seshasayee, Aswin Sai Narain","given":"Aswin Sai Narain","family":"Seshasayee"},{"display":"Singh, Amit","roleDisplay":"VerfasserIn","role":"aut","family":"Singh","given":"Amit"}],"title":[{"title":"Bioenergetic reprogramming of macrophages reduces drug tolerance in Mycobacterium tuberculosis","title_sort":"Bioenergetic reprogramming of macrophages reduces drug tolerance in Mycobacterium tuberculosis"}],"recId":"1945015411","language":["eng"],"type":{"bibl":"article-journal","media":"Online-Ressource"},"note":["Online veröffentlicht: 23. Oktober 2025","Gesehen am 08.12.2025"],"name":{"displayForm":["Vikas Yadav, Sarthak Sahoo, Nitish Malhotra, Richa Mishra, Sreesa Sreedharan, Raju S. Rajmani, Siva Shanmugam, Radha K. Shandil, Shridhar Narayanan, Vivek V. Thacker, Sunil Laxman, Mohit Kumar Jolly, Aswin Sai Narain Seshasayee & Amit Singh"]},"id":{"eki":["1945015411"],"doi":["10.1038/s41467-025-64407-w"]},"origin":[{"dateIssuedKey":"2025","dateIssuedDisp":"23 October 2025"}],"relHost":[{"physDesc":[{"extent":"Online-Ressource"}],"origin":[{"publisherPlace":"[London] ; [London]","publisher":"Springer Nature ; Nature Publishing Group UK","dateIssuedDisp":"[2010]-"}],"id":{"issn":["2041-1723"],"eki":["626457688"],"zdb":["2553671-0"]},"type":{"media":"Online-Ressource","bibl":"periodical"},"note":["Gesehen am 13.06.24"],"disp":"Bioenergetic reprogramming of macrophages reduces drug tolerance in Mycobacterium tuberculosisNature Communications","recId":"626457688","language":["eng"],"pubHistory":["2010-"],"part":{"text":"16(2025), Artikel-ID 9370, Seite 1-20","volume":"16","extent":"20","year":"2025","pages":"1-20"},"title":[{"title":"Nature Communications","title_sort":"Nature Communications"}]}],"physDesc":[{"noteIll":"Illustrationen","extent":"20 S."}]} | ||
| SRT | |a YADAVVIKASBIOENERGET2320 | ||