N-acylated derivatives of sulfamethoxazole block Chlamydia fatty acid synthesis and interact with FabF [PublishAheadOfPrint]

The type II fatty acid synthesis (FASII) pathway is essential for bacterial lipid biosynthesis and continues to be a promising target for novel antibacterial compounds. Recently, it has been demonstrated that Chlamydia is capable of FASII and this pathway is indispensable for Chlamydia growth. Previously, a high-content-screen was performed with C. trachomatis infected cells and acylated sulfonamides were identified as potent growth inhibitors of the bacteria. C. trachomatis strains resistant to acylated sulfonamides were isolated by serial passaging a wild type strain in low compound concentrations. Results from whole genome sequencing of ten isolates from two independent drug resistant populations revealed that accumulated mutations in fabF were predominant. Protein-small molecule interaction studies showed that acylated sulfonamides directly bind to recombinant FabF in vitro and treatment of C. trachomatis infected HeLa cells with the compounds leads to a decrease in the synthesis of Chlamydia fatty acids. This work demonstrates the importance of FASII for Chlamydia development and may lead towards the development of new antimicrobials.

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