Trehalose catalytic shift inherently enhances phenotypic heterogeneity and multidrug resistance in Mycobacterium tuberculosis

Jae Jin Lee, Daniel H. Swanson, Sun-Kyung Lee, Stephanie Dihardjo, Gi Yong Lee, Sree Gelle, Hoon Je Seong, Emily R. M. Bravo, Zachary E. Taylor, Michael S. Nieuwenhze, Abhyudai Singh, Jong-Seok Lee, Seokyong Eum, SangNae Cho, Benjamin M. Swarts and Hyungjin Eoh ()
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Jae Jin Lee: University of Southern California
Daniel H. Swanson: Central Michigan University
Sun-Kyung Lee: International Tuberculosis Research Center
Stephanie Dihardjo: University of Southern California
Gi Yong Lee: University of Southern California
Sree Gelle: University of Southern California
Hoon Je Seong: Kunsan National University
Emily R. M. Bravo: Central Michigan University
Zachary E. Taylor: Baylor University
Michael S. Nieuwenhze: Baylor University
Abhyudai Singh: University of Delaware
Jong-Seok Lee: Kunsan National University
Seokyong Eum: Kunsan National University
SangNae Cho: Kunsan National University
Benjamin M. Swarts: Central Michigan University
Hyungjin Eoh: University of Southern California

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Drug-resistance (DR) in bacteria often develops through the repetitive formation of drug-tolerant persisters, which survive antibiotics without genetic changes. It is unclear whether Mycobacterium tuberculosis (Mtb), the bacterium that causes tuberculosis (TB), undergoes a similar transitioning process. Recent studies highlight changes in trehalose metabolism as crucial for persister formation and drug resistance. Here, we observe that mutants lacking trehalose catalytic shift activity exhibited fewer DR mutants due to decreased persisters. This shift enhances Mtb survival during antibiotic treatment by increasing metabolic heterogeneity and drug tolerance, facilitating drug resistance. Rifampicin (RIF)-resistant bacilli display cross-resistance to other antibiotics linked to higher trehalose catalytic shift, explaining how multidrug resistance (MDR) can follow RIF-resistance. In particular, the HN878 W-Beijing strain exhibits higher trehalose catalytic shift, increasing MDR risk. Both genetic and pharmacological inactivation of this shift reduces persister formation and MDR development, suggesting trehalose catalytic shift as a potential therapeutic target to combat TB resistance.

Date: 2025
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DOI: 10.1038/s41467-025-61703-3

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