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

TitleTransient drug-tolerance and permanent drug-resistance rely on the trehalose-catalytic shift in Mycobacterium tuberculosis.
Publication TypeJournal Article
Year of Publication2019
AuthorsLee JJin, Lee S-K, Song N, Nathan TO, Swarts BM, Eum S-Y, Ehrt S, Cho S-N, Eoh H
JournalNat Commun
Volume10
Issue1
Pagination2928
Date Published2019 07 02
ISSN2041-1723
KeywordsAdenosine Triphosphate, Anti-Bacterial Agents, Bacterial Proteins, Catalysis, Drug Resistance, Multiple, Bacterial, Glucosyltransferases, Humans, Mycobacterium tuberculosis, Trehalose, Tuberculosis
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.

DOI10.1038/s41467-019-10975-7
Alternate JournalNat Commun
PubMed ID31266959
PubMed Central IDPMC6606615
Grant ListR15 AI117670 / AI / NIAID NIH HHS / United States
R21 AI139386 / AI / NIAID NIH HHS / United States

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