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

• Published in: Antimicrobial agents and chemotherapy Vol. 61; no. 10
• Main Authors: Mojica, Sergio A, Salin, Olli, Bastidas, Robert J, Sunduru, Naresh, Hedenström, Mattias, Andersson, C David, Núñez-Otero, Carlos, Engström, Patrik, Valdivia, Raphael H, Elofsson, Mikael, Gylfe, Åsa
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 01.10.2017
• Subjects: Acylation - drug effects; Adamantane - pharmacology; Aminobenzoates - pharmacology; Anilides - pharmacology; Animals; Anti-Bacterial Agents; Anti-Bacterial Agents - pharmacology; antimicrobial agents; Cell Line, Tumor; Cercopithecus aethiops; Cerulenin - pharmacology; Chlamydia Infections - drug therapy; Chlamydia Infections - microbiology; Chlamydia trachomatis; Chlamydia trachomatis - drug effects; Chlamydia trachomatis - genetics; Chlamydia trachomatis - metabolism; drug targets; FAS; Fatty Acid Synthase, Type II; Fatty Acid Synthase, Type II - genetics; Fatty Acid Synthase, Type II - metabolism; Fatty Acid Synthesis Inhibitors; Fatty Acid Synthesis Inhibitors - pharmacology; Fatty Acids; Fatty Acids - biosynthesis; HeLa Cells; Humans; Mechanisms of Action: Physiological Effects; Sulfamethoxazole; Sulfamethoxazole - pharmacology; Triclosan - pharmacology; Vero Cells; drug targets; FAS; Chlamydia trachomatis; antimicrobial agents
• ISSN: 0066-4804; 1098-6596; 1098-6596
• DOI: 10.1128/AAC.00716-17

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.