Macrophage infectivity potentiator protein, a peptidyl prolyl cis-trans isomerase, essential for Coxiella burnetii growth and pathogenesis.

Autor: Debowski AW; Marshall Centre for Infectious Disease Research and Training, School of Biomedical Sciences, The University of Western Australia, Nedlands, Western Australia, Australia.; School of Molecular Sciences, The University of Western Australia, Crawley, Western Australia, Australia., Bzdyl NM; Marshall Centre for Infectious Disease Research and Training, School of Biomedical Sciences, The University of Western Australia, Nedlands, Western Australia, Australia., Thomas DR; Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Australia.; Infection and Immunity Program, Department of Microbiology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Australia., Scott NE; Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Australia., Jenkins CH; Defence Science and Technology Laboratory, Porton Down, Salisbury, United Kingdom., Iwasaki J; Marshall Centre for Infectious Disease Research and Training, School of Biomedical Sciences, The University of Western Australia, Nedlands, Western Australia, Australia.; Wesfarmers Centre for Vaccines and Infectious Diseases, Telethon Kids Institute, University of Western Australia, Nedlands, Western Australia, Australia.; Centre for Child Health Research, University of Western Australia, Perth, Western Australia, Australia., Kibble EA; Marshall Centre for Infectious Disease Research and Training, School of Biomedical Sciences, The University of Western Australia, Nedlands, Western Australia, Australia.; School of Veterinary and Life Sciences, Murdoch University, Perth, WA, Australia.; DMTC Limited, Level 1, Kew, Australia., Khoo CA; Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Australia., Scheuplein NJ; Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, Würzburg, Germany., Seibel PM; School of Molecular Sciences, The University of Western Australia, Crawley, Western Australia, Australia., Lohr T; Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, Würzburg, Germany., Metters G; Defence Science and Technology Laboratory, Porton Down, Salisbury, United Kingdom.; Department of Biosciences, University of Exeter, Geoffrey Pope Building, Stocker Road, Exeter, United Kingdom., Bond CS; School of Molecular Sciences, The University of Western Australia, Crawley, Western Australia, Australia., Norville IH; Defence Science and Technology Laboratory, Porton Down, Salisbury, United Kingdom.; Department of Biosciences, University of Exeter, Geoffrey Pope Building, Stocker Road, Exeter, United Kingdom., Stubbs KA; School of Molecular Sciences, The University of Western Australia, Crawley, Western Australia, Australia., Harmer NJ; Department of Biosciences, University of Exeter, Geoffrey Pope Building, Stocker Road, Exeter, United Kingdom.; Living Systems Institute, Stocker Road Exeter, United Kingdom., Holzgrabe U; Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, Würzburg, Germany., Newton HJ; Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Australia.; Infection and Immunity Program, Department of Microbiology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Australia., Sarkar-Tyson M; Marshall Centre for Infectious Disease Research and Training, School of Biomedical Sciences, The University of Western Australia, Nedlands, Western Australia, Australia.
Jazyk: angličtina
Zdroj: PLoS pathogens [PLoS Pathog] 2023 Jul 03; Vol. 19 (7), pp. e1011491. Date of Electronic Publication: 2023 Jul 03 (Print Publication: 2023).
DOI: 10.1371/journal.ppat.1011491
Abstrakt: 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 CbMip 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 CbMip. 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 H2O2 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 CbMip is warranted and offer potential as novel therapeutics against this pathogen.
Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: The authors MST, UH, NB, AWD, NJS, and TL are named as inventors in Patent PCT/AU2023/050201.
(Copyright: © 2023 Debowski et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje