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

• DOI: 10.1371/journal.ppat.1011491
• Publication Date: 2023-07-03T17:29:01Z
• Authors: Aleksandra W. Deb...; Nicole M. Bzdyl; David R. Thomas; Nichollas E. Scott; Christopher H. Je...; Jua Iwasaki; Emily A. Kibble; Chen Ai Khoo; Nicolas J. Scheup...; Pamela M. Seibel; Theresa Lohr; Georgie Metters; Charles S. Bond; Isobel H. Norville; Keith A. Stubbs; Nicholas J. Harmer; Ulrike Holzgrabe; Hayley J. Newton; Mitali Sarkar-Tyson
• Keywords: Coxiella burnetii; Q fever; Infectivity

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, effective but has high risk of severe adverse reactions, limiting its use as countermeasure to contain outbreaks. Therefore, it essential identify new drug targets treat this infection. Macrophage infectivity potentiator (Mip) proteins catalyse folding proline-containing through their peptidyl prolyl cis-trans isomerase (PPIase) activity have been shown play an important role in virulence several pathogenic bacteria. To date Mip protein C. pathogenesis not investigated. This study demonstrates CbMip likely be burnetii. pipecolic acid derived compounds, SF235 AN296, utility targeting other from bacteria, demonstrate inhibitory activities against CbMip. These compounds were found significantly inhibit replication HeLa THP-1 cells. Furthermore, AN296 also exhibit antibiotic properties virulent (Phase I) avirulent II) forms Nine Mile Strain axenic culture. Comparative proteomics, presence revealed alterations stress responses with H2O2 sensitivity assays validating inhibition increases oxidative stress. In addition, vivo improved survival Galleria mellonella infected results suggest unlike required for development more potent inhibitors warranted offer potential novel therapeutics pathogen.