Inhibition of bacterial FMN transferase: A potential avenue for countering antimicrobial resistance

Abstract

Antibiotic resistance is a challenge for the control of bacterial infections. In an effort to explore unconventional avenues for antibacterial drug development, we focused on the FMN-transferase activity of the enzyme Ftp from the syphilis spirochete, Treponema pallidum (Ftp_Tp). This enzyme, which is only found in prokaryotes and trypanosomatids, post-translationally modifies proteins in the periplasm, covalently linking FMN (from FAD) to proteins that typically are important for establishing an essential electrochemical gradient across the cytoplasmic membrane. As such, Ftp inhibitors potentially represent a new class of antimicrobials. Previously, we showed that AMP is both a product of the Ftp_tp-catalyzed reaction and an inhibitor of the enzyme. As a preliminary step in exploiting this property to develop a novel Ftp_Tp inhibitor, we have used structural and solution studies to examine the inhibitory and enzyme-binding properties of several adenine-based nucleosides, with particular focus on the 2-position of the purine ring. Implications for future drug design are discussed.

Mining the Flavoproteome of Brucella ovis, the Brucellosis Causing Agent in Ovis aries

“…In agreement, a comparative metabolomics study in B. melitensis also pointed to synthase as an attractive target ( 106 ). Others with certain homology to the here-identified thioredoxin-disulphide reductase ( 107 ) or FAD:protein FMN transferase are also considered antimicrobial targets ( 108 ). Noticeably, Table 4 includes an important number of the B. ovis flavoproteins for which the exact physiological function is difficult to envisage.…”