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.
| Original language | English |
|---|---|
| Number of pages | 1 |
| Journal | Nature communications |
| Volume | 10 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 2019 Jul 2 |
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All Science Journal Classification (ASJC) codes
- Chemistry(all)
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)
Cite this
}
Transient drug-tolerance and permanent drug-resistance rely on the trehalose-catalytic shift in Mycobacterium tuberculosis. / Lee, Jae Jin; Lee, Sun Kyung; Song, Naomi; Nathan, Temitope O.; Swarts, Benjamin M.; Eum, Seok Yong; Ehrt, Sabine; Cho, Sangnae; Eoh, Hyungjin.
In: Nature communications, Vol. 10, No. 1, 02.07.2019.Research output: Contribution to journal › Article
TY - JOUR
T1 - Transient drug-tolerance and permanent drug-resistance rely on the trehalose-catalytic shift in Mycobacterium tuberculosis
AU - Lee, Jae Jin
AU - Lee, Sun Kyung
AU - Song, Naomi
AU - Nathan, Temitope O.
AU - Swarts, Benjamin M.
AU - Eum, Seok Yong
AU - Ehrt, Sabine
AU - Cho, Sangnae
AU - Eoh, Hyungjin
PY - 2019/7/2
Y1 - 2019/7/2
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-019-10975-7
DO - 10.1038/s41467-019-10975-7
M3 - Article
VL - 10
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
ER -