Poster Presentation Australian Society for Microbiology Annual Scientific Meeting 2023

Testing the efficacy of novel macrophage infectivity potentiator protein inhibitors against Chlamydia trachomatis. (#123)

Aleksandra W Debowski 1 2 3 , Nicolas J Scheuplein 4 , Ulrike Holzgrabe 4 , Mitali Sarkar-Tyson 1 3
  1. Marshall Centre for Infectious Diseases, School of Biomedical Sciences, University of Western Australia, Nedlands, WA, Australia
  2. School of Molecular Sciences, University of Western Australia, Crawley, WA, Australia
  3. DMTC Limited, Kew, Vic, Australia
  4. Institute of Pharmacy and Food Chemistry, University of Würzburg, Würzburg, Germany

Chlamydia trachomatis is a Gram-negative, obligate intracellular pathogen and the leading cause of bacterial sexually transmitted infections and infectious blindness in developed countries. If left untreated, these infections can lead to severe health complications, including pelvic inflammatory disease, and infertility. Chlamydial species have a unique and complex biphasic life cycle, where they are infectious during only one life stage. They have an elementary body (EB) form which is the infectious form and adapted for extracellular survival, and a reticulate body (RB) form which is involved in intracellular growth and replication inside a specialized compartment within mammalian cells, termed an inclusion.

Macrophage infectivity potentiator (Mip) proteins catalyse the folding of proline-containing proteins through their peptidyl prolyl cis-trans isomerase activity. Mips have been shown to play an important role in the virulence of several pathogenic bacteria but to date limited work has been conducted to investigate the role of Mip in C. trachomatis infections (1). In this study we used a virulent strain belonging to serovar L2, C. trachomatis L2/434/BU, which causes invasive sexually transmitted infections that can disseminate to the regional draining lymph nodes (2). We screened novel Mip inhibitors against C. trachomatis in in vitro cell infection assays, and evaluated inclusion numbers and size as well as progeny infectivity by epifluorescence microscopy and immunoblot analysis.

Mip inhibitors were found to significantly reduce the intracellular replication of C. trachomatis in HeLa cells. Furthermore, Mip inhibitors also interfered with the developmental cycle of C. trachomatis, resulting in a significant reduction in the number of infectious progeny. Our data shows that Mip activity is important for C. trachomatis replication and development, suggesting that inhibition of Mip may represent a novel target for antimicrobial therapies for Chlamydia infections.

 

  1. 1. Scheuplein NJ, Bzdyl NM, Kibble EA, Lohr T, Holzgrabe U, Sarkar-Tyson M. Targeting Protein Folding: A Novel Approach for the Treatment of Pathogenic Bacteria. J Med Chem. 2020;63(22):13355-88.
  2. 2. Faris R, Andersen SE, McCullough A, Gourronc F, Klingelhutz AJ, Weber MM. Chlamydia trachomatis Serovars Drive Differential Production of Proinflammatory Cytokines and Chemokines Depending on the Type of Cell Infected. Frontiers in cellular and infection microbiology. 2019;9:399.