PMID- 36354071
OWN - NLM
STAT- MEDLINE
DCOM- 20221111
LR  - 20221206
IS  - 1769-714X (Electronic)
IS  - 1286-4579 (Linking)
VI  - 24
IP  - 8
DP  - 2022 Nov-Dec
TI  - Mycobacterium tuberculosis ketol-acid reductoisomerase down-regulation affects 
      its ability to persist, and its survival in macrophages and in mice.
PG  - 105000
LID - S1286-4579(22)00070-3 [pii]
LID - 10.1016/j.micinf.2022.105000 [doi]
AB  - Branched-chain amino acids (BCAAs) leucine, isoleucine and valine biosynthetic 
      pathways have been reported from plants, fungi and bacteria including 
      Mycobacterium tuberculosis (Mtb) but are absent in animals. This makes 
      interventions with BCAAs biosynthesis an attractive proposition for 
      antimycobacterial drug discovery. In the present study, Mycobacterium 
      tuberculosis H37Ra (Mtb-Ra) ketol-acid reductoisomerase encoding ORF MRA_3031 was 
      studied to establish its role in Mtb-Ra growth and survival. Recombinant 
      knockdown (KD) and complemented (KDC) strains along with wild-type (WT) Mtb-Ra 
      were studied under in-vitro and ex-vivo conditions. KD was defective for survival 
      inside macrophages and showed time dependent decrease in its colony forming unit 
      (CFU) counts, while, WT and KDC showed time dependent increase in CFUs, after 
      macrophage infection. Also, KD showed reduced ability to form persister cells, 
      had altered membrane permeability against ethidium bromide and nile red dyes, and 
      had reduced biofilm maturation, compared to WT and KDC. The in-vivo studies 
      showed that KD infected mice had lower CFU counts in lungs, compared to WT. In 
      summary Mtb shows survival deficit in macrophages and in mice after ketol-acid 
      reductoisomerase down-regulation.
CI  - Copyright (c) 2022 Institut Pasteur. Published by Elsevier Masson SAS. All rights 
      reserved.
FAU - Singh, Nirbhay
AU  - Singh N
AD  - Molecular Microbiology and Immunology Division, CSIR-Central Drug Research 
      Institute, B.S. 10/1, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow 
      226031, India.
FAU - Chauhan, Anu
AU  - Chauhan A
AD  - Molecular Microbiology and Immunology Division, CSIR-Central Drug Research 
      Institute, B.S. 10/1, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow 
      226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 
      201002, India.
FAU - Kumar, Ram
AU  - Kumar R
AD  - Molecular Microbiology and Immunology Division, CSIR-Central Drug Research 
      Institute, B.S. 10/1, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow 
      226031, India.
FAU - Singh, Sudheer Kumar
AU  - Singh SK
AD  - Molecular Microbiology and Immunology Division, CSIR-Central Drug Research 
      Institute, B.S. 10/1, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow 
      226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 
      201002, India. Electronic address: sudheer_singh@cdri.res.in.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20221027
PL  - France
TA  - Microbes Infect
JT  - Microbes and infection
JID - 100883508
RN  - EC 1.1.1.86 (Ketol-Acid Reductoisomerase)
SB  - IM
MH  - Mice
MH  - Animals
MH  - *Mycobacterium tuberculosis/metabolism
MH  - Ketol-Acid Reductoisomerase/metabolism
MH  - Down-Regulation
MH  - Macrophages/microbiology
MH  - Biofilms
OTO - NOTNLM
OT  - Branched-chain amino acids
OT  - Ketol-acid reductoisomerase
OT  - Macrophage and in-vivo survival
OT  - Mycobacterium tuberculosis
OT  - Permeability
OT  - Persistence
COIS- Declaration of competing interest Authors declare that there is no competing 
      interest.
EDAT- 2022/11/11 06:00
MHDA- 2022/11/15 06:00
CRDT- 2022/11/10 05:53
PHST- 2022/01/17 00:00 [received]
PHST- 2022/04/08 00:00 [revised]
PHST- 2022/05/04 00:00 [accepted]
PHST- 2022/11/10 05:53 [entrez]
PHST- 2022/11/11 06:00 [pubmed]
PHST- 2022/11/15 06:00 [medline]
AID - S1286-4579(22)00070-3 [pii]
AID - 10.1016/j.micinf.2022.105000 [doi]
PST - ppublish
SO  - Microbes Infect. 2022 Nov-Dec;24(8):105000. doi: 10.1016/j.micinf.2022.105000. 
      Epub 2022 Oct 27.