PMID- 31218537 OWN - NLM STAT- MEDLINE DCOM- 20201103 LR - 20201103 IS - 1618-1905 (Electronic) IS - 1139-6709 (Linking) VI - 23 IP - 2 DP - 2020 May TI - The preclinical candidate indole-2-carboxamide improves immune responses to Mycobacterium tuberculosis infection in healthy subjects and individuals with type 2 diabetes. PG - 161-170 LID - 10.1007/s10123-019-00086-0 [doi] AB - A novel group of agents known as the indole-2-carboxamides (often referred to as indoleamides) have been shown to demonstrate high antimycobacterial activity. Studies have demonstrated that the best indoleamides possess desirable ADME/Tox properties, with less adverse effects and increased efficacy against both MDR-TB (multi-drug resistant TB) and XDR-TB (extensively drug-resistant TB). The primary mechanism of killing Mycobacterium tuberculosis (Mtb) by indoleamides is by disrupting the function of the essential mycolic acid transporter MmpL3 protein (Mycobacterial membrane protein Large 3). Therefore, targeting this essential mycobacterial transporter by small molecules opens new possibility for the development of novel and effective anti-TB agents. In the present study, we characterized the effects of indoleamides in altering the viability of Mtb in an in vitro granuloma model using immune cells derived from healthy subjects and those with type 2 diabetes mellitus (T2DM). Our results indicate that treatment with the best indoleamide 3 resulted in a significant reduction in the viability of Mtb in both THP-1 macrophages as well as in granulomas derived from healthy individuals and subjects with T2DM. Graphical Abstract. FAU - Cao, Ruoqiong AU - Cao R AD - College of Life Sciences, Hebei University, Baoding, 071000, Hebei, China. AD - Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, 91766-1854, USA. FAU - Islamoglu, Hicret AU - Islamoglu H AD - Department of Biological Sciences, California State Polytechnic University, Pomona, CA, 91768, USA. FAU - Teskey, Garrett AU - Teskey G AD - Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, CA, 91766-1854, USA. FAU - Gyurjian, Karo AU - Gyurjian K AD - Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, 91766-1854, USA. FAU - Abrahem, Rachel AU - Abrahem R AD - Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, CA, 91766-1854, USA. FAU - Onajole, Oluseye K AU - Onajole OK AD - Department of Biological, Physical and Health Sciences, Roosevelt University, 425 S. Wabash Avenue, Chicago, IL, 60605, USA. FAU - Lun, Shichun AU - Lun S AD - Johns Hopkins School of Medicine, JHU Center for TB Research, 1550 Orleans St, Baltimore, MD, USA. FAU - Bishai, William AU - Bishai W AD - Johns Hopkins School of Medicine, JHU Center for TB Research, 1550 Orleans St, Baltimore, MD, USA. FAU - Kozikowski, Alan P AU - Kozikowski AP AD - StarWise Therapeutics LLC, University Research Park, Madison, WI, USA. FAU - Fraix, Marcel P AU - Fraix MP AD - Departments of Physical Medicine and Rehabilitation and Neuromusculoskeletal Medicine, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, 91766-1854, USA. FAU - Sathananthan, Airani AU - Sathananthan A AD - Department of Internal Medicine, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, 91766-1854, USA. FAU - Zhong, Li AU - Zhong L AD - College of Life Sciences, Hebei University, Baoding, 071000, Hebei, China. AD - Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, 91766-1854, USA. FAU - Stec, Jozef AU - Stec J AD - Department of Pharmaceutical Sciences, College of Pharmacy, Marshall B. Ketchum University, 2575 Yorba Linda Boulevard, Fullerton, CA, 92831, USA. FAU - Venketaraman, Vishwanath AU - Venketaraman V AD - Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, 91766-1854, USA. vvenketaraman@westernu.edu. AD - Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, CA, 91766-1854, USA. vvenketaraman@westernu.edu. LA - eng GR - AI 37856/Foundation for the National Institutes of Health (US)/ GR - HL 133190/Foundation for the National Institutes of Health/ GR - No. 81272444/National Natural Science Foundation of China/ GR - 81472744/National Natural Science Foundation of China (CN)/ PT - Journal Article DEP - 20190619 PL - Switzerland TA - Int Microbiol JT - International microbiology : the official journal of the Spanish Society for Microbiology JID - 9816585 RN - 0 (Antitubercular Agents) RN - 0 (Cytokines) RN - 0 (Indoles) SB - IM MH - Antitubercular Agents/pharmacology MH - Cytokines/drug effects/metabolism MH - Diabetes Mellitus, Type 2/immunology MH - Drug Discovery MH - Granuloma/drug therapy/metabolism/microbiology MH - Healthy Volunteers MH - Humans MH - Immunity, Cellular/drug effects MH - Immunity, Innate/*drug effects MH - Indoles/*pharmacology MH - Mycobacterium tuberculosis/*drug effects MH - THP-1 Cells MH - Tuberculosis/drug therapy OTO - NOTNLM OT - Cytokines OT - Drug discovery OT - Infection immunity OT - Innate immunity OT - Intracellular parasitology OT - Mycobacterium tuberculosis EDAT- 2019/06/21 06:00 MHDA- 2020/11/04 06:00 CRDT- 2019/06/21 06:00 PHST- 2019/02/21 00:00 [received] PHST- 2019/05/22 00:00 [accepted] PHST- 2019/05/07 00:00 [revised] PHST- 2019/06/21 06:00 [pubmed] PHST- 2020/11/04 06:00 [medline] PHST- 2019/06/21 06:00 [entrez] AID - 10.1007/s10123-019-00086-0 [pii] AID - 10.1007/s10123-019-00086-0 [doi] PST - ppublish SO - Int Microbiol. 2020 May;23(2):161-170. doi: 10.1007/s10123-019-00086-0. Epub 2019 Jun 19.