Transient drug-tolerance and permanent drug-resistance rely on the trehalose-catalytic shift in Mycobacterium tuberculosis

Jae Jin Lee, Sun-Kyung Lee, Naomi Song, Temitope O. Nathan, Benjamin M. Swarts, Seok-Yong Eum, Sabine Ehrt, Sang-Nae Cho and Hyungjin Eoh ()
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Jae Jin Lee: University of Southern California
Sun-Kyung Lee: International Tuberculosis Research Center
Naomi Song: Weill Cornell Medical College
Temitope O. Nathan: Central Michigan University
Benjamin M. Swarts: Central Michigan University
Seok-Yong Eum: International Tuberculosis Research Center
Sabine Ehrt: Weill Cornell Medical College
Sang-Nae Cho: International Tuberculosis Research Center
Hyungjin Eoh: University of Southern California

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: Abstract Stochastic formation of Mycobacterium tuberculosis (Mtb) persisters achieves a high level of antibiotic-tolerance and serves as a source of multidrug-resistant (MDR) mutations. As conventional treatment is not effective against infections by persisters and MDR-Mtb, novel therapeutics are needed. Several approaches were proposed to kill persisters by altering their metabolism, obviating the need to target active processes. Here, we adapted a biofilm culture to model Mtb persister-like bacilli (PLB) and demonstrated that PLB underwent trehalose metabolism remodeling. PLB use trehalose as an internal carbon to biosynthesize central carbon metabolism intermediates instead of cell surface glycolipids, thus maintaining levels of ATP and antioxidants. Similar changes were identified in Mtb following antibiotic-treatment, and MDR-Mtb as mechanisms to circumvent antibiotic effects. This suggests that trehalose metabolism is associated not only with transient drug-tolerance but also permanent drug-resistance, and serves as a source of adjunctive therapeutic options, potentiating antibiotic efficacy by interfering with adaptive strategies.

Date: 2019
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DOI: 10.1038/s41467-019-10975-7

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