TY - JOUR
T1 - The 1, 2-ethylenediamine SQ109 protects against tuberculosis by promoting M1 macrophage polarization through the p38 MAPK pathway
AU - Singh, Mona
AU - Kumar, Santosh
AU - Singh, Baldeep
AU - Jain, Preeti
AU - Kumari, Anjna
AU - Pahuja, Isha
AU - Chaturvedi, Shivam
AU - Prasad, Durbaka Vijay Raghava
AU - Dwivedi, Ved Prakash
AU - Das, Gobardhan
N1 - Funding Information:
We acknowledge the support of Dbt-Supported Tuberculosis Aerosol Challenge Facility At The International Centre for Genetic Engineering and Biotechnology (ICGEB, New Delhi, India) and their staff in accomplishing this work. MS acknowledges SERB, DST for providing the National Post-Doctoral Fellowship (PDF/2021/001238). We would also like to acknowledge Prof Luc Van Kaer for his critical reading of the manuscript.
Funding Information:
We acknowledge the support of Dbt-Supported Tuberculosis Aerosol Challenge Facility At The International Centre for Genetic Engineering and Biotechnology (ICGEB, New Delhi, India) and their staff in accomplishing this work. MS acknowledges SERB, DST for providing the National Post-Doctoral Fellowship (PDF/2021/001238). We would also like to acknowledge Prof Luc Van Kaer for his critical reading of the manuscript.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/7/28
Y1 - 2022/7/28
N2 - Directly Observed Treatment Short-course (DOTs), is an effective and widely recommended treatment for tuberculosis (TB). The antibiotics used in DOTs, are immunotoxic and impair effector T cells, increasing the risk of re-infections and reactivation. Multiple reports suggest that addition of immune-modulators along with antibiotics improves the effectiveness of TB treatment. Therefore, drugs with both antimicrobial and immunomodulatory properties are desirable. N1-(Adamantan-2-yl)-N2-[(2E)-3,7-dimethylocta-2,6-dien-1-yl]ethane-1,2-diamine (SQ109) is an asymmetric diamine derivative of adamantane, that targets Mycobacterial membrane protein Large 3 (MmpL3). SQ109 dissipates the transmembrane electrochemical proton-gradient necessary for cell-wall biosynthesis and bacterial activity. Here, we examined the effects of SQ109 on host-immune responses using a murine TB model. Our results suggest the pro-inflammatory nature of SQ109, which instigates M1-macrophage polarization and induces protective pro-inflammatory cytokines through the p38-MAPK pathway. SQ109 also promotes Th1 and Th17-immune responses that inhibit the bacillary burden in a murine model of TB. These findings put forth SQ109 as a potential-adjunct to TB antibiotic therapy.
AB - Directly Observed Treatment Short-course (DOTs), is an effective and widely recommended treatment for tuberculosis (TB). The antibiotics used in DOTs, are immunotoxic and impair effector T cells, increasing the risk of re-infections and reactivation. Multiple reports suggest that addition of immune-modulators along with antibiotics improves the effectiveness of TB treatment. Therefore, drugs with both antimicrobial and immunomodulatory properties are desirable. N1-(Adamantan-2-yl)-N2-[(2E)-3,7-dimethylocta-2,6-dien-1-yl]ethane-1,2-diamine (SQ109) is an asymmetric diamine derivative of adamantane, that targets Mycobacterial membrane protein Large 3 (MmpL3). SQ109 dissipates the transmembrane electrochemical proton-gradient necessary for cell-wall biosynthesis and bacterial activity. Here, we examined the effects of SQ109 on host-immune responses using a murine TB model. Our results suggest the pro-inflammatory nature of SQ109, which instigates M1-macrophage polarization and induces protective pro-inflammatory cytokines through the p38-MAPK pathway. SQ109 also promotes Th1 and Th17-immune responses that inhibit the bacillary burden in a murine model of TB. These findings put forth SQ109 as a potential-adjunct to TB antibiotic therapy.
KW - Adamantane/pharmacology
KW - Animals
KW - Antitubercular Agents/therapeutic use
KW - Ethylenediamines/metabolism
KW - Macrophages
KW - Mice
KW - Mycobacterium tuberculosis/metabolism
KW - Tuberculosis/drug therapy
KW - p38 Mitogen-Activated Protein Kinases/metabolism
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U2 - 10.1038/s42003-022-03693-2
DO - 10.1038/s42003-022-03693-2
M3 - Article
C2 - 35902694
AN - SCOPUS:85135159769
SN - 2399-3642
VL - 5
SP - 759
JO - Communications Biology
JF - Communications Biology
IS - 1
M1 - 759
ER -