Targeting Virulence as an Approach to Bacterial Pathogenesis: Efforts Towards the Development of Chemical Biology Tools and Anti-Chlamydial Therapeutics

Abstract

Chlamydia trachomatis, an obligate intracellular bacterium, is the most common sexually transmitted pathogen in the developed world as well as the leading cause of infectious blindness worldwide. The development of comprehensive therapeutics for infections is impeded by the fact that relatively little is known about the molecular underpinnings of C. trachomatis pathogenesis, as this microorganism has been historically refractory to genetic manipulation. Recent studies strongly suggest that the survival of C. trachomatis is dependent upon the secretion of a number of effector proteins and enzymes that interfere with host signaling. However, the exact role of many of these effector molecules in chlamydial pathogenesis remains elusive. Thus, there is a need for the discovery and development of chemical biology tools that can be used to probe the function of chlamydial effectors, and in turn possibly reveal therapeutic targets for antibiotic development. Here we report efforts toward the design, synthesis, and evaluation of small molecules as probes for chlamydial effectors. Combined with the utilization of bioinformatics and proteomics techniques, we have made progress towards investigating the role of chlamydial effector enzymes in pathogenesis.