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Sci Transl Med. 2014 Nov 19;6(263):263ra159. doi: 10.1126/scitranslmed.3009885.

Metformin as adjunct antituberculosis therapy.

Author information

1
Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore. amit_singhal@immunol.a-star.edu.sg gennaro_delibero@immunol.a-star.edu.sg.
2
Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore.
3
Tuberculosis Control Unit, Tan Tock Seng Hospital, Singapore 308089, Singapore.
4
Department of Endocrinology, Tan Tock Seng Hospital, Singapore 308433, Singapore. Singapore Institute for Clinical Sciences, A*STAR, Singapore 117609, Singapore.
5
Public Health Research Institute at New Jersey Medical School, Rutgers University, Newark, NJ 07103, USA. New York City College of Technology, Brooklyn, NY 11201, USA.
6
Public Health Research Institute at New Jersey Medical School, Rutgers University, Newark, NJ 07103, USA.
7
Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore. Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore.
8
Public Health Research Institute at New Jersey Medical School, Rutgers University, Newark, NJ 07103, USA. Bill & Melinda Gates Foundation, Seattle, WA 98109, USA.
9
Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore. University Hospital Basel, University of Basel, Basel 4031, Switzerland. amit_singhal@immunol.a-star.edu.sg gennaro_delibero@immunol.a-star.edu.sg.

Abstract

The global burden of tuberculosis (TB) morbidity and mortality remains immense. A potential new approach to TB therapy is to augment protective host immune responses. We report that the antidiabetic drug metformin (MET) reduces the intracellular growth of Mycobacterium tuberculosis (Mtb) in an AMPK (adenosine monophosphate-activated protein kinase)-dependent manner. MET controls the growth of drug-resistant Mtb strains, increases production of mitochondrial reactive oxygen species, and facilitates phagosome-lysosome fusion. In Mtb-infected mice, use of MET ameliorated lung pathology, reduced chronic inflammation, and enhanced the specific immune response and the efficacy of conventional TB drugs. Moreover, in two separate human cohorts, MET treatment was associated with improved control of Mtb infection and decreased disease severity. Collectively, these data indicate that MET is a promising candidate host-adjunctive therapy for improving the effective treatment of TB.

PMID:
25411472
DOI:
10.1126/scitranslmed.3009885
[Indexed for MEDLINE]
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