N-Acylated Derivatives of Sulfamethoxazole Block Chlamydia Fatty Acid Synthesis and Interact with FabF

Abstract

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 is capable of FASII and this pathway is indispensable for growth. Previously, a high-content screen with -infected cells was performed, and acylated sulfonamides were identified to be potent growth inhibitors of the bacteria. strains resistant to acylated sulfonamides were isolated by serial passage of a wild-type strain in the presence of low compound concentrations. Results from whole-genome sequencing of 10 isolates from two independent drug-resistant populations revealed that mutations that accumulated in were predominant. Studies of the interaction between the FabF protein and small molecules showed that acylated sulfonamides directly bind to recombinant FabF and treatment of-infected HeLa cells with the compounds leads to a decrease in the synthesis of fatty acids. This work demonstrates the importance of FASII for development and may lead to the development of new antimicrobials.

Synthesis and Antichlamydial Activity of Molecules Based on Dysregulators of Cylindrical Proteases

“…Noteworthy is the seminal work of Almqvist et al that sought to inhibit chlamydial growth by blocking the glucose-6-phosphate pathway. , This group has developed a novel class of thiazolino-2-pyridones that show remarkable inhibitory activity and low toxicity toward mammalian cells. Elofsson and co-workers also reported another intriguing approach focused on blocking the type II fatty acid synthesis pathway (FAS II) . The same group has prepared compounds with dual activity by combining key features from active compounds into hybrid systems .…”

“…Elofsson and coworkers also reported another intriguing approach focused on blocking the type II fatty acid synthesis pathway (FAS II). 21 The same group has prepared compounds with dual activity by combining key features from active compounds into hybrid systems. 22 These important works highlight the importance of designing compounds that affect nontraditional bacterial targets to eradicate this pathogen.…”

“…Notably, none of our compounds showed inhibitory activity against these species in a preliminary screening at 32 μg/mL (Table S2). To further investigate their selectivity, we subjected S. aureus JE2 and E. coli K12 to concentrations up to 256 μg/mL of compounds 11,21,25,28,35,37,40,42, and once again, bacterial death was not observed. These results indicate that the compounds may be selective for Chlamydia.…”

Evaluating the Antibiotic Susceptibility of Chlamydia – New Approaches for in Vitro Assays

“…However, a larger sample size is necessary to confirm this finding. Moreover, these and other C. suis field strains should also be investigated for resistance to N-acylated sulfonamide derivatives because, despite sharing the structural core with sulfamethoxazole and sulfafurazole, they operate via a distinct working mechanism ( Marwaha et al, 2014 ; Mojica et al, 2017 ): These antibiotics do not affect folate synthesis but instead bind directly to the 3-oxoacyl-[acyl carrier protein (ACP) synthase II (FabF)] thus inhibiting the essential type II fatty acid synthesis (FASII) pathway.…”

Synthesis, Spectroscopic Characterization, and In Vitro Antibacterial Evaluation of Novel Functionalized Sulfamidocarbonyloxyphosphonates

“…Another approach utilizes the amide exchange of a sulfamide by heating with an amine [ 11 ]. In parallel, many synthetic efforts have also focused on sulfonamide derivatives that have shown great potency to inhibit important biological targets such as cox-2, carbonic anhydrase (e.g., isoenzymes I, II, VII, IX), and NaV1.7, or to block, for example, the Chlamydia fatty acid synthesis [ 12 , 13 , 14 , 15 , 16 ].…”