title: Metformin as adjunct antituberculosis therapy.
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.
authors.affiliation: 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.
authors.forename: Amit
authors.initials: A
authors.lastname: Singhal
authors.affiliation: Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore.
authors.forename: Liu
authors.initials: L
authors.lastname: Jie
authors.affiliation: Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore.
authors.forename: Pavanish
authors.initials: P
authors.lastname: Kumar
authors.affiliation: Tuberculosis Control Unit, Tan Tock Seng Hospital, Singapore 308089, Singapore.
authors.forename: Gan Suay
authors.initials: GS
authors.lastname: Hong
authors.affiliation: Department of Endocrinology, Tan Tock Seng Hospital, Singapore 308433, Singapore. Singapore Institute for Clinical Sciences, A*STAR, Singapore 117609, Singapore.
authors.forename: Melvin Khee-Shing
authors.initials: MK
authors.lastname: Leow
authors.affiliation: Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore.
authors.forename: Bhairav
authors.initials: B
authors.lastname: Paleja
authors.affiliation: 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.
authors.forename: Liana
authors.initials: L
authors.lastname: Tsenova
authors.affiliation: Public Health Research Institute at New Jersey Medical School, Rutgers University, Newark, NJ 07103, USA.
authors.forename: Natalia
authors.initials: N
authors.lastname: Kurepina
authors.affiliation: Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore.
authors.forename: Jinmiao
authors.initials: J
authors.lastname: Chen
authors.affiliation: Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore.
authors.forename: Francesca
authors.initials: F
authors.lastname: Zolezzi
authors.affiliation: Public Health Research Institute at New Jersey Medical School, Rutgers University, Newark, NJ 07103, USA.
authors.forename: Barry
authors.initials: B
authors.lastname: Kreiswirth
authors.affiliation: 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.
authors.forename: Michael
authors.initials: M
authors.lastname: Poidinger
authors.affiliation: Tuberculosis Control Unit, Tan Tock Seng Hospital, Singapore 308089, Singapore.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Chee
authors.affiliation: Public Health Research Institute at New Jersey Medical School, Rutgers University, Newark, NJ 07103, USA. Bill & Melinda Gates Foundation, Seattle, WA 98109, USA.
authors.forename: Gilla
authors.initials: G
authors.lastname: Kaplan
authors.affiliation: Tuberculosis Control Unit, Tan Tock Seng Hospital, Singapore 308089, Singapore.
authors.forename: Yee Tang
authors.initials: YT
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Gennaro
authors.initials: G
authors.lastname: De Libero
mesh_terms: D006801:Humans; D008687:Metformin / Q000494:pharmacology / Q000627:therapeutic use*; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development; D017382:Reactive Oxygen Species / Q000378:metabolism; D014376:Tuberculosis / Q000188:drug therapy* / Q000276:immunology
chemical_list: D017382:Reactive Oxygen Species; D008687:Metformin