Broad-spectrum in vitro activity of macrophage infectivity potentiator inhibitors against Gram-negative bacteria and Leishmania major.

Autor:	Iwasaki J; Marshall Centre for Infectious Disease Research and Training, School of Biomedical Sciences, The University of Western Australia, Perth, Western Australia, 6008, Australia.; Wesfarmers Centre for Vaccines and Infectious Diseases, Telethon Kids Institute, University of Western Australia, Nedlands, Western Australia, 6008, Australia.; Centre for Child Health Research, University of Western Australia, Perth, Western Australia, 6008, Australia., Lorimer DD; Seattle Structural Genomics Center for Infectious Disease, 307 Westlake Avenue North, Seattle, WA, 98109, USA.; Beryllium, Inc., 7869 NE Day Road West, Bainbridge Island, WA 98110, USA., Vivoli-Vega M; Department of Biosciences, Geoffrey Pope Building, Stocker Road, Exeter, EX4 4QD, UK.; Living Systems Institute, Stocker Road, Exeter, EX4 4QD, UK., Kibble EA; Marshall Centre for Infectious Disease Research and Training, School of Biomedical Sciences, The University of Western Australia, Perth, Western Australia, 6008, Australia.; School of Veterinary and Life Sciences, Murdoch University, Perth, WA, Australia.; DMTC Limited, Level 2, 24 Wakefield St, Hawthorn, VIC 3122, Australia., Peacock CS; Marshall Centre for Infectious Disease Research and Training, School of Biomedical Sciences, The University of Western Australia, Perth, Western Australia, 6008, Australia., Abendroth J; Seattle Structural Genomics Center for Infectious Disease, 307 Westlake Avenue North, Seattle, WA, 98109, USA.; Beryllium, Inc., 7869 NE Day Road West, Bainbridge Island, WA 98110, USA., Mayclin SJ; Seattle Structural Genomics Center for Infectious Disease, 307 Westlake Avenue North, Seattle, WA, 98109, USA.; Beryllium, Inc., 7869 NE Day Road West, Bainbridge Island, WA 98110, USA., Dranow DM; Seattle Structural Genomics Center for Infectious Disease, 307 Westlake Avenue North, Seattle, WA, 98109, USA.; Beryllium, Inc., 7869 NE Day Road West, Bainbridge Island, WA 98110, USA., Pierce PG; Seattle Structural Genomics Center for Infectious Disease, 307 Westlake Avenue North, Seattle, WA, 98109, USA.; Beryllium, Inc., 7869 NE Day Road West, Bainbridge Island, WA 98110, USA., Fox D; Seattle Structural Genomics Center for Infectious Disease, 307 Westlake Avenue North, Seattle, WA, 98109, USA.; Beryllium, Inc., 7869 NE Day Road West, Bainbridge Island, WA 98110, USA., Lewis M; Marshall Centre for Infectious Disease Research and Training, School of Biomedical Sciences, The University of Western Australia, Perth, Western Australia, 6008, Australia., Bzdyl NM; Marshall Centre for Infectious Disease Research and Training, School of Biomedical Sciences, The University of Western Australia, Perth, Western Australia, 6008, Australia., Kristensen SS; Marshall Centre for Infectious Disease Research and Training, School of Biomedical Sciences, The University of Western Australia, Perth, Western Australia, 6008, Australia., Inglis TJJ; Department of Microbiology, PathWest Laboratory Medicine, Nedlands, WA 6009, Australia.; Medical School, University of Western Australia, Nedlands, WA 6009, Australia., Kahler CM; Marshall Centre for Infectious Disease Research and Training, School of Biomedical Sciences, The University of Western Australia, Perth, Western Australia, 6008, Australia., Bond CS; School of Molecular Sciences, The University of Western Australia, Perth, Western Australia, 6009, Australia., Hasenkopf A; Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, 97074 Würzburg, Germany., Seufert F; Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, 97074 Würzburg, Germany., Schmitz J; Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, 97074 Würzburg, Germany., Marshall LE; Defence Science and Technology Laboratory, Porton Down, Salisbury, UK., Scott AE; Defence Science and Technology Laboratory, Porton Down, Salisbury, UK., Norville IH; Defence Science and Technology Laboratory, Porton Down, Salisbury, UK., Myler PJ; Seattle Structural Genomics Center for Infectious Disease, 307 Westlake Avenue North, Seattle, WA, 98109, USA., Holzgrabe U; Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, 97074 Würzburg, Germany., Harmer NJ; Department of Biosciences, Geoffrey Pope Building, Stocker Road, Exeter, EX4 4QD, UK.; Living Systems Institute, Stocker Road, Exeter, EX4 4QD, UK., Sarkar-Tyson M; Marshall Centre for Infectious Disease Research and Training, School of Biomedical Sciences, The University of Western Australia, Perth, Western Australia, 6008, Australia.
Jazyk:	angličtina
Zdroj:	The Journal of antimicrobial chemotherapy [J Antimicrob Chemother] 2022 May 29; Vol. 77 (6), pp. 1625-1634.
DOI:	10.1093/jac/dkac065
Abstrakt:	Background: The macrophage infectivity potentiator (Mip) protein, which belongs to the immunophilin superfamily, is a peptidyl-prolyl cis/trans isomerase (PPIase) enzyme. Mip has been shown to be important for virulence in a wide range of pathogenic microorganisms. It has previously been demonstrated that small-molecule compounds designed to target Mip from the Gram-negative bacterium Burkholderia pseudomallei bind at the site of enzymatic activity of the protein, inhibiting the in vitro activity of Mip. Objectives: In this study, co-crystallography experiments with recombinant B. pseudomallei Mip (BpMip) protein and Mip inhibitors, biochemical analysis and computational modelling were used to predict the efficacy of lead compounds for broad-spectrum activity against other pathogens. Methods: Binding activity of three lead compounds targeting BpMip was verified using surface plasmon resonance spectroscopy. The determination of crystal structures of BpMip in complex with these compounds, together with molecular modelling and in vitro assays, was used to determine whether the compounds have broad-spectrum antimicrobial activity against pathogens. Results: Of the three lead small-molecule compounds, two were effective in inhibiting the PPIase activity of Mip proteins from Neisseria meningitidis, Klebsiella pneumoniae and Leishmania major. The compounds also reduced the intracellular burden of these pathogens using in vitro cell infection assays. Conclusions: These results indicate that Mip is a novel antivirulence target that can be inhibited using small-molecule compounds that prove to be promising broad-spectrum drug candidates in vitro. Further optimization of compounds is required for in vivo evaluation and future clinical applications. (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)
Databáze:	MEDLINE
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