An unnatural amino acid dependent, conditional Pseudomonas vaccine prevents bacterial infection

Michael Pigula, Yen-Chung Lai, Minseob Koh, Christian S. Diercks, Thomas F. Rogers, David A. Dik () and Peter G. Schultz ()
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Michael Pigula: Scripps Research
Yen-Chung Lai: Scripps Research
Minseob Koh: Pusan National University
Christian S. Diercks: Scripps Research
Thomas F. Rogers: Scripps Research
David A. Dik: Scripps Research
Peter G. Schultz: Scripps Research

Nature Communications, 2024, vol. 15, issue 1, 1-9

Abstract: Abstract Live vaccines are ideal for inducing immunity but suffer from the need to attenuate their pathogenicity or replication to preclude the possibility of escape. Unnatural amino acids (UAAs) provide a strategy to engineer stringent auxotrophies, yielding conditionally replication incompetent live bacteria with excellent safety profiles. Here, we engineer Pseudomonas aeruginosa to maintain auxotrophy for the UAA p-benzoyl-l-phenylalanine (BzF) through its incorporation into the essential protein DnaN. In vivo evolution using an Escherichia coli-based two-hybrid selection system enabled engineering of a mutant DnaN homodimeric interface completely dependent on a BzF-specific interaction. This engineered strain, Pa Vaccine, exhibits undetectable escape frequency (

Date: 2024
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DOI: 10.1038/s41467-024-50843-7

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