AUTHOR=Yao Jiangwei , Rock Charles O. 

TITLE=Therapeutic Targets in Chlamydial Fatty Acid and Phospholipid Synthesis

JOURNAL=Frontiers in Microbiology

VOLUME=9

YEAR=2018

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2018.02291

DOI=10.3389/fmicb.2018.02291

ISSN=1664-302X

ABSTRACT=<p><italic>Chlamydia trachomatis</italic> is an obligate intracellular pathogen with a reduced genome reflecting its host cell dependent life style. However, <italic>C. trachomatis</italic> has retained all of the genes required for fatty acid and phospholipid synthesis that are present in free-living bacteria. <italic>C. trachomatis</italic> assembles its cellular membrane using its own biosynthetic machinery utilizing glucose, isoleucine, and serine. This pathway produces disaturated phospholipid molecular species containing a branched-chain 15-carbon fatty acid in the 2-position, which are distinct from the structures of host phospholipids. The enoyl reductase step (FabI) is a target for antimicrobial drug discovery, and the developmental candidate, AFN-1252, blocks the activity of <italic>Ct</italic>FabI. The x-ray crystal structure of the <italic>Ct</italic>FabI•NADH•AFN-1252 ternary complex reveals the interactions between the drug, protein, and cofactor. AFN-1252 treatment of <italic>C. trachomatis</italic>-infected HeLa cells at any point in the infection cycle reduces infectious titers, and treatment at the time of infection prevents the first cell division. Fatty acid synthesis is essential for <italic>C. trachomatis</italic> proliferation within its eukaryotic host, and <italic>Ct</italic>FabI is a validated therapeutic target against <italic>C. trachomatis</italic>.</p>