Unveiling the role of BON domain-containing proteins in antibiotic resistance

Abstract

The alarming rise of antibiotic-resistant Gram-negative bacteria poses a global health crisis. Their unique outer membrane restricts antibiotic access. While diffusion porins are well-studied, the role of BON domain-containing proteins (BDCPs) in resistance remains unexplored. We analyze protein databases, revealing widespread BDCP distribution across environmental bacteria. We further describe their conserved core domain structure, a key for understanding antibiotic transport. Elucidating the genetic and biochemical basis of BDCPs offers a novel target to combat antibiotic resistance and restore bacterial susceptibility to antibiotics.

Keywords: BON domain-containing protein; antibiotic resistance; cell envelope; pathogens; structure and function.

Figure 1

Phylogenetic tree analysis of various sources of BDCP. These 463 protein sequences were aligned using MUSCLE implemented in the phylogenetic analysis program MEGA-X (Kumar et al., 2018), which was subsequently used as the input for constructing a neighbor-joining phylogenetic tree to infer evolutionary relationships for these protein families. Different letters with different numbers (e.g., A1, A2, A3, B1, B2, and B3) on the clade represent different sources of bacteria (see Supplementary Excel form). The same letters with different numbers (e.g., A1-1, A1-2, and A1-3) represent that they come from the same genus but different species.

Figure 2

Multiple sequence alignment of these BDCPs from various pathogens. Similar residues are written with black bold characters and boxed in yellow. The same residues are written with white characters and boxed in red background.

Figure 3

Display and comparison among different BDCPs identified from pathogenic bacteria. (A) Macroscopic comparison between BDCPs from several pathogens. The strain name, Uniprot entry number, schematic diagram of BDCPs (S, signal peptide; B, BON domain), and amino acid number were shown from left to right. (B) 3D structures of these above-mentioned BDCPs in pathogens. They were modeled using AlphaFold and consisted of α-helix (blue) the β-sheet (red), and a random coil (purple). The 3D structures of proteins (from left to right in each row) were collected from Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Acinetobacter baumannii, Burkholderia multivorans, Vibrio parahaemolyticus, Legionella pneumophila, Burkholderia cenocepacia, Burkholderia pseudomallei, Sinorhizobium meliloti, and Salmonella enterica.

Figure 4

Potential mechanism of BDCPs-mediated antibiotic resistance. (A) View of OMPs monomer from the side. (B) View of BDCP with different special directions from K. pneumoniae embedded in the cell's outer membrane. (C) A model of BDCP-mediated development of antibiotic resistance. It describes the localization, oligomerization, and potential function of a typical BDCP throughout the outer membrane.