Subclass IId bacteriocins targeting Man-PTS--structural diversity and implications for receptor interaction and antimicrobial activity

Abstract

The bacterial mannose phosphotransferase system (Man-PTS) mediates uptake of selected monosaccharides. Simultaneously, it is a receptor for diverse bacteriocins such as subclass IIa pediocin-like bacteriocins and some subclass IId ones (garvicins ABCQ, lactococcins ABZ, BacSJ, ubericin K, and angicin). So far, no attempt has been made to categorize this ever-expanding group of bacteriocins. Here, we identified Man-PTS as a receptor for a number of novel bacteriocins and demonstrated that they all belong to a large family of Man-PTS-binding non-pediocin-like peptides. Based on amino acid sequence similarities between members of this family, we propose their classification into five groups. This classification conveniently distinguishes bacteriocins with specific structures and properties regarding their spectrum of antimicrobial activity and pattern of interaction with Man-PTS. With respect to the latter, we indicate individual amino acid residues or regions of Man-PTS and the bacteriocin responsible for their interaction. In Man-PTS these residues localize to the exterior of the transport complex, specifically the extracellular loop of the so-called Vmotif domain containing regions {gamma} and/or {gamma}+, and to the interior of the transport complex, specifically the interface between the Core and Vmotif domains. Finally, we propose that while the bacteriocins from separate groups display specific binding patterns to Man-PTS, the general mechanism of their interaction with the receptor is universal despite significant differences in their predicted structures, i.e., after initial docking on the bacterial cell through an interaction with the Man-PTS regions {gamma} and/or {gamma}+, they pull away its Core and Vmotif from one another to form a pore across the membrane. Significance statementBacteriocins show potential as natural and safe food preservatives and next-generation antibiotics. However, ensuring their safe future use requires primarily the identification of bacteriocin receptors and a detailed understanding of the molecular mechanisms of their selective recognition and binding. Here, we demonstrate the paramount role of Man-PTS in the binding of various non-studied and nearly non-homologous subclass IId bacteriocins with different activity spectra and bacteriocin-receptor binding patterns. Exploiting Man-PTS as a target for novel antimicrobials could be a promising strategy of killing diverse bacterial pathogens, including their antibiotic-resistant strains.