Structural basis and dynamics of multidrug recognition in a minimal bacterial multidrug resistance system

Abstract

Significance Multidrug recognition is an important phenomenon that is not well understood. TipA, a bacterial transcriptional regulator, constitutes a minimal multidrug resistance system against numerous thiopeptide antibiotics. We show that motions in the millisecond to microsecond time range form the basis of the TipA multidrug recognition mechanism. This may be common to many multidrug recognition systems. The discovery that the structural antibiotic motifs essential for binding to TipA and to the ribosome are identical makes the multidrug recognition mechanism of TipA a useful model for ribosomal thiopeptide binding and current antibiotic drug development.

YcaO-Dependent Posttranslational Amide Activation: Biosynthesis, Structure, and Function

“…345 However, these thiopeptides do still activate TipA demonstrating that TipA stimulation is not equivalent to antibiotic activity. 346 …”

“…493, 494 Thiopeptides of various sizes and topologies are recognized by a common four-ring motif. 346 Upon binding, dehydroamino acids often present in thiopeptides can undergo a Michael-like addition with Cys residues of TipA present within the flexible binding pocket. 346, 495–497 However, thiopeptides with a 29-membered macrocycles lack the conserved four-ring motif.…”

“…Fittingly, they also do not induce or bind to TipA. 346 Additionally, because TipA is highly responsive to thiopeptides, its induction has been applied in thiopeptide discovery. 383, 384, 390, 394 …”

Molecular insights into antibiotic resistance - how a binding protein traps albicidin

“…Another prominent and well-described MerR system is the thiopeptide-binding protein TipA (thiostrepton-induced protein A) from Streptomyces lividans 25 , 26 . The tipA gene encodes for two alternate in-frame translation products: the long form TipAL consisting of the N-terminal HTH DNA-binding domain (TipAN), and the shorter C-terminal thiopeptide drug-binding domain (TipAS) 27 . Drug binding to TipAL leads to an upregulation of its own expression and confers resistance against several thiopeptide antibiotics, e.g., thiostrepton, nosiheptide, and promothiocin A 16 .…”

“…Drug binding to TipAL leads to an upregulation of its own expression and confers resistance against several thiopeptide antibiotics, e.g., thiostrepton, nosiheptide, and promothiocin A 16 . Previously, Grzesiek and co-workers have solved the solution structure of TipAS bound to various thiopeptides 16 , 27 , which for the first time gave insights into binding determinants and domain dynamics of the protein.…”