Glutamine metabolism inhibition has dual immunomodulatory and antibacterial activities against Mycobacterium tuberculosis

Sadiya Parveen, Jessica Shen, Shichun Lun, Liang Zhao, Jesse Alt, Benjamin Koleske, Robert D. Leone, Rana Rais, Jonathan D. Powell, John R. Murphy, Barbara S. Slusher and William R. Bishai ()
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Sadiya Parveen: Johns Hopkins School of Medicine
Jessica Shen: Johns Hopkins School of Medicine
Shichun Lun: Johns Hopkins School of Medicine
Liang Zhao: Johns Hopkins School of Medicine
Jesse Alt: Johns Hopkins University
Benjamin Koleske: Johns Hopkins School of Medicine
Robert D. Leone: Johns Hopkins School of Medicine
Rana Rais: Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine
Jonathan D. Powell: The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins School of Medicine
John R. Murphy: Johns Hopkins School of Medicine
Barbara S. Slusher: Johns Hopkins School of Medicine
William R. Bishai: Johns Hopkins School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract As one of the most successful human pathogens, Mycobacterium tuberculosis (Mtb) has evolved a diverse array of determinants to subvert host immunity and alter host metabolic patterns. However, the mechanisms of pathogen interference with host metabolism remain poorly understood. Here we show that a glutamine metabolism antagonist, JHU083, inhibits Mtb proliferation in vitro and in vivo. JHU083-treated mice exhibit weight gain, improved survival, a 2.5 log lower lung bacillary burden at 35 days post-infection, and reduced lung pathology. JHU083 treatment also initiates earlier T-cell recruitment, increased proinflammatory myeloid cell infiltration, and a reduced frequency of immunosuppressive myeloid cells when compared to uninfected and rifampin-treated controls. Metabolomic analysis of lungs from JHU083-treated Mtb-infected mice reveals citrulline accumulation, suggesting elevated nitric oxide (NO) synthesis, and lowered levels of quinolinic acid which is derived from the immunosuppressive metabolite kynurenine. JHU083-treated macrophages also produce more NO potentiating their antibacterial activity. When tested in an immunocompromised mouse model of Mtb infection, JHU083 loses its therapeutic efficacy suggesting the drug’s host-directed effects are likely to be predominant. Collectively, these data reveal that JHU083-mediated glutamine metabolism inhibition results in dual antibacterial and host-directed activity against tuberculosis.

Date: 2023
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DOI: 10.1038/s41467-023-43304-0

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