Atomic structures of a bacteriocin targeting Gram-positive bacteria

Xiaoying Cai, Yao He, Iris Yu, Anthony Imani, Dean Scholl, Jeff F. Miller () and Z. Hong Zhou ()
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Xiaoying Cai: University of California, Los Angeles (UCLA)
Yao He: University of California, Los Angeles (UCLA)
Iris Yu: University of California, Los Angeles (UCLA)
Anthony Imani: University of California, Los Angeles (UCLA)
Dean Scholl: Pylum Biosciences
Jeff F. Miller: University of California, Los Angeles (UCLA)
Z. Hong Zhou: University of California, Los Angeles (UCLA)

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract Due to envelope differences between Gram-positive and Gram-negative bacteria, engineering precision bactericidal contractile nanomachines requires atomic-level understanding of their structures; however, only those killing Gram-negative bacteria are currently known. Here, we report the atomic structures of an engineered diffocin, a contractile syringe-like molecular machine that kills the Gram-positive bacterium Clostridioides difficile. Captured in one pre-contraction and two post-contraction states, each structure fashions six proteins in the bacteria-targeting baseplate, two proteins in the energy-storing trunk, and a collar linking the sheath with the membrane-penetrating tube. Compared to contractile machines targeting Gram-negative bacteria, major differences reside in the baseplate and contraction magnitude, consistent with target envelope differences. The multifunctional hub-hydrolase protein connects the tube and baseplate and is positioned to degrade peptidoglycan during penetration. The full-length tape measure protein forms a coiled-coil helix bundle homotrimer spanning the entire diffocin. Our study offers mechanical insights and principles for designing potent protein-based precision antibiotics.

Date: 2024
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DOI: 10.1038/s41467-024-51038-w

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