Functional and Structural Diversity of Bacterial Contact-Dependent Growth Inhibition Effectors

Abstract

Bacteria live in complex communities and environments, competing for space and nutrients. Within their niche habitats, bacteria have developed various inter-bacterial mechanisms to compete and communicate. One such mechanism is contact-dependent growth inhibition (CDI). CDI is found in many Gram-negative bacteria, including several pathogens. These CDI+ bacteria encode a CdiB/CdiA two-partner secretion system that delivers inhibitory toxins into neighboring cells upon contact. Toxin translocation results in the growth inhibition of closely related strains and provides a competitive advantage to the CDI+ bacteria. CdiB, an outer-membrane protein, secretes CdiA onto the surface of the CDI+ bacteria. When CdiA interacts with specific target-cell receptors, CdiA delivers its C-terminal toxin region (CdiA-CT) into the target-cell. CdiA-CT toxin proteins display a diverse range of toxic functions, such as DNase, RNase, or pore-forming toxin activity. CDI+ bacteria also encode an immunity protein, CdiI, that specifically binds and neutralizes its cognate CdiA-CT, protecting the CDI+ bacteria from auto-inhibition. In Gram-negative bacteria, toxin/immunity (CdiA-CT/CdiI) pairs have highly variable sequences and functions, with over 130 predicted divergent toxin/immunity complex families. In this review, we will discuss biochemical and structural advances made in the characterization of CDI. This review will focus on the diverse array of CDI toxin/immunity complex structures together with their distinct toxin functions. Additionally, we will discuss the most recent studies on target-cell recognition and toxin entry, along with the discovery of a new member of the CDI loci. Finally, we will offer insights into how these diverse toxin/immunity complexes could be harnessed to fight human diseases.

Pathogenicity assessment of Shiga toxin-producing Escherichia coli strains isolated from wild birds in a major agricultural region in California

“…CDI, a type V delivery system, uses a long β-helical cell surface protein to contact the target cells and deliver a growth inhibition signal in target cells ( Ikryannikova et al, 2020 ). CDI is widespread in gram-negative bacteria including several important human pathogens and plays a role in interbacterial competition and communication ( Cuthbert et al, 2022 ). A recent study demonstrated that CDI was a key virulence determinant in the human pathogen Pseudomonas aeruginosa due to its contribution to toxicity in cultured mammalian cells and lethality in mouse model system due to bacteremia ( Allen et al, 2020 ).…”

The Love and Hate Relationship between T5SS and Other Secretion Systems in Bacteria

“…Rhs from Dickeya dadantii is an effector secreted by T6SS, which has a conserved central region and variable N- and C-terminal regions [ 101 ]. The 3′ region of rhs encodes a recombination of a C-terminal toxin tRNase domain and its downstream gene, while the 5′ end of rhs encodes a T5SS contact-dependent inhibition (CDI) passenger domain, which enables cell surface expression and transfer of the C-terminal toxic effector domain to inhibit the growth of E. coli prey cells [ 102 , 103 ]. In Gram-negative bacteria, both T5SS and T6SS secrete toxins to the extracellular space, which antagonize other microorganisms and thus seize the living environment [ 104 ].…”

Friend or Foe: Protein Inhibitors of DNA Gyrase

“…Many essential bacterial pathways are known because of their targeting by molecular "warfare", such as being in competition for resources between cells within bacterial cultures [1][2][3]. These strategies include secretion systems that introduce effector molecules into competitors, rendering the recipient cells inactive via interaction with essential targets [4,5]. Similarly, mobile genetic elements (MGEs) utilize strategies to target essential pathways to mediate retention within host cells (for recent reviews, please see [6][7][8][9]).…”