In:
PLOS Pathogens, Public Library of Science (PLoS), Vol. 19, No. 7 ( 2023-7-3), p. e1011491-
Abstract:
Coxiella burnetii is a Gram-negative intracellular pathogen that causes the debilitating disease Q fever, which affects both animals and humans. The only available human vaccine, Q-Vax, is effective but has a high risk of severe adverse reactions, limiting its use as a countermeasure to contain outbreaks. Therefore, it is essential to identify new drug targets to treat this infection. Macrophage infectivity potentiator (Mip) proteins catalyse the folding of proline-containing proteins through their peptidyl prolyl cis - trans isomerase (PPIase) activity and have been shown to play an important role in the virulence of several pathogenic bacteria. To date the role of the Mip protein in C . burnetii pathogenesis has not been investigated. This study demonstrates that Cb Mip is likely to be an essential protein in C . burnetii . The pipecolic acid derived compounds, SF235 and AN296, which have shown utility in targeting other Mip proteins from pathogenic bacteria, demonstrate inhibitory activities against Cb Mip. These compounds were found to significantly inhibit intracellular replication of C . burnetii in both HeLa and THP-1 cells. Furthermore, SF235 and AN296 were also found to exhibit antibiotic properties against both the virulent (Phase I) and avirulent (Phase II) forms of C . burnetii Nine Mile Strain in axenic culture. Comparative proteomics, in the presence of AN296, revealed alterations in stress responses with H 2 O 2 sensitivity assays validating that Mip inhibition increases the sensitivity of C . burnetii to oxidative stress. In addition, SF235 and AN296 were effective in vivo and significantly improved the survival of Galleria mellonella infected with C . burnetii . These results suggest that unlike in other bacteria, Mip in C . burnetii is required for replication and that the development of more potent inhibitors against Cb Mip is warranted and offer potential as novel therapeutics against this pathogen.
Type of Medium:
Online Resource
ISSN:
1553-7374
DOI:
10.1371/journal.ppat.1011491
DOI:
10.1371/journal.ppat.1011491.g001
DOI:
10.1371/journal.ppat.1011491.g002
DOI:
10.1371/journal.ppat.1011491.g003
DOI:
10.1371/journal.ppat.1011491.g004
DOI:
10.1371/journal.ppat.1011491.g005
DOI:
10.1371/journal.ppat.1011491.g006
DOI:
10.1371/journal.ppat.1011491.g007
DOI:
10.1371/journal.ppat.1011491.g008
DOI:
10.1371/journal.ppat.1011491.g009
DOI:
10.1371/journal.ppat.1011491.t001
DOI:
10.1371/journal.ppat.1011491.t002
DOI:
10.1371/journal.ppat.1011491.s001
DOI:
10.1371/journal.ppat.1011491.s002
DOI:
10.1371/journal.ppat.1011491.s003
DOI:
10.1371/journal.ppat.1011491.s004
DOI:
10.1371/journal.ppat.1011491.s005
DOI:
10.1371/journal.ppat.1011491.s006
DOI:
10.1371/journal.ppat.1011491.s007
DOI:
10.1371/journal.ppat.1011491.s008
DOI:
10.1371/journal.ppat.1011491.s009
DOI:
10.1371/journal.ppat.1011491.s010
DOI:
10.1371/journal.ppat.1011491.s011
DOI:
10.1371/journal.ppat.1011491.s012
DOI:
10.1371/journal.ppat.1011491.s013
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2023
detail.hit.zdb_id:
2205412-1
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