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De novo engineering of a bacterial lifestyle program

Abstract

Synthetic biology has shown remarkable potential to program living microorganisms for applications. However, a notable discrepancy exists between the current engineering practice—which focuses predominantly on planktonic cells—and the ubiquitous observation of microbes in nature that constantly alternate their lifestyles on environmental variations. Here we present the de novo construction of a synthetic genetic program that regulates bacterial life cycle and enables phase-specific gene expression. The program is orthogonal, harnessing an engineered protein from 45 candidates as the biofilm matrix building block. It is also highly controllable, allowing directed biofilm assembly and decomposition as well as responsive autonomous planktonic-biofilm phase transition. Coupling to synthesis modules, it is further programmable for various functional realizations that conjugate phase-specific biomolecular production with lifestyle alteration. This work establishes a versatile platform for microbial engineering across physiological regimes, thereby shedding light on a promising path for gene circuit applications in complex contexts.

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Fig. 1: Characterization of matrix scaffold proteins.
Fig. 2: Controllable biofilm assembly with engineered gene circuits.
Fig. 3: Directed biofilm decomposition through rational protein design.
Fig. 4: Autonomous transition between the planktonic and biofilm phases.
Fig. 5: Applications of the lifestyle program for phase-specific biomolecule production.
Fig. 6: Engineered function realization decoupled to phase transition.

Data availability

Protein accession numbers (UniProt) are listed in Supplementary Table 1. Sequences for promoters and genes are provided in Supplementary Table 3. Source data are provided with this paper.

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Acknowledgements

This work was supported by the Office of Naval Research (grant no. N00014-16-1-2525).

Author information

Authors and Affiliations

Authors

Contributions

T.L. conceived the project. T.L. and P.S.S. designed the study. W.K. screened and characterized biofilm-forming proteins, constructed circuits for controllable biofilm formation and engineered P45 variants for biofilm dispersal. W.K. and Y.Q. developed platform for phase transition and function realization. W.K. and Y.Q. carried out experiments for auto-aggregation, biofilm quantification, product measurement and collected the data. W.K., Y.Q. and T.L. analyzed the data. T.L. and W.K. wrote the article with input from P.S.S. and Y.Q.

Corresponding author

Correspondence to Ting Lu.

Ethics declarations

Competing interests

T.L., Y.Q. and W.K. have filed a provisional patent application (application number: 63/404,971) on the platform described in this text. The remaining authors declare no competing interests.

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Nature Chemical Biology thanks Seok Hoon Hong and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Additional characterization of biofilm matrix proteins.

a, Plasmid for constitutive expression of the biofilm matrix proteins. b, Thickness of the biofilms formed on the surface of non-tissue culture treated 96-well plate by the library of 45 L. lactis strains that express predicted surface proteins (P1 to P45). c, SEM images of the biofilms formed by the strains encoding the proteins P6, P13, P25 and P40. Data are presented as mean ± s.d. from 3 independent experiments, and representative pictures from different samples are shown.

Source data

Extended Data Fig. 2 Dispersal of synthetic biofilms from plastic surfaces.

a, Protease-based dispersal of the biofilms made of P6, P25, P40 and P45. The biofilms on a polystyrene cell culture treated 96 well plate were directly quantified by crystal violet staining without any treatment, or treated by PBS or proteinase K (10 µg ml−1) for 2 hours at room temperature before being quantified. Data are presented as mean ± s.d. (n = 3 independent experiments). b, SEM images of intact, untreated biofilms and proteinase K-treated biofilms on polystyrene plastic sheets.

Source data

Extended Data Fig. 3 Additional characterizations of the P45 variants.

a, Quantification of biofilms formed on the polystyrene cell culture treated 96 well plate for the variants IS1-IS5. b, Images of test tubes containing the cultures of the variants at pH 7.4 and pH 5.0. c, Quantification of the aggregation ability of the variants at pH 7.4 and pH 5.0. For all panels, the strain P45 was used as a control. Data are presented as mean ± s.d. from n = 3 independent experiments. Representative pictures from different samples are shown.

Source data

Extended Data Fig. 4 Protease secretion and in vitro biofilm dispersal.

a, Protease secretion by L. lactis NZ9000 upon nisin induction. Lane 1, protein ladder. Lane 2, control without protease secretion. Lane 3 and 4, Protease A. Lane 5 and 6, Protease B. Lane 7 and 8, Protease C. Black arrow indicates the band of Usp45. Red arrow indicates Protease A. Green arrow indicates Protease B. Blue arrow indicates Protease C. The absence of the Usp45 band in Lane 5–8 suggests that Proteases B and C both exhibit proteolytic activity to digest Usp45. b, Inhibition of the IS5 biofilm by the supernatants of the protease-secreting strains. Overnight culture of IS5 was diluted with fresh medium to the OD600 of 0.04, then 120 µl of the diluted culture was added to a cell culture treated 96-well plate. 30 µl of L. lactis NZ9000 supernatants containing different proteases were added into the IS5 culture. Biofilm thickness was measured after growth for 24 hours. Data are presented as mean ± s.d. from 3 independent experiments.

Source data

Extended Data Fig. 5 Plasmid maps and control experiments for planktonic-biofilm transition.

a, Map of the plasmid IS5-Zn-gfp-prob. b, Map of the plasmid P45-Zn-gfp. c, Gene circuit of the plasmid P45-Zn-gfp. d-i, State transition experiments for the strain carrying the plasmid P45-Zn-gfp under different temporal patterns of zinc availability. Compared to the case of the strain carrying the plasmid IS5-Zn-gfp-prob (Fig. 4), the biofilm of the P45-Zn-gfp loaded strain cannot be decomposed once it forms. Experimental data are presented as mean ± s.d. from 3 independent experiments.

Source data

Extended Data Fig. 6 Increased antibiotic resistance coupled with biofilm formation.

a, Design of the gene circuit IS5-orf29-P7-Erm-Zn-gfp-prob. Building on the circuit IS5-Zn-gfp-prob, this system was established by introducing the transcriptional activator gene Orf29 at the downstream of IS5 and using the cognate promoter P7 to drive the expression of the erythromycin (Erm) resistance gene. b, Validations of the biofilm-coupled Erm resistance with colony forming unit counting. Cells containing the circuit IS5-orf29-P7-Erm-Zn-gfp-prob or the circuit IS5-Zn-gfp-prob were pre-cultured in the GM17/Cm/Zn media to be induced to the planktonic state or in the GM17/Cm/EDTA media to be induced to the biofilm state for 36 h with inoculations to fresh medium occurring every 12 h. Then, cell cultures with OD600 of 1.0 were serially diluted by 100–106 folds, and 5 µl of diluted cultures were added onto the agar plate supplemented with Cm to select all cells and the agar plate with Erm to select cells with the Erm resistance. c,d, State transitions of the strain carrying the circuit IS5-orf29-P7-Erm-Zn-gfp-prob under different temporal patterns of zinc availability. The Erm resistance was coupled with biofilm formation. e,f, State transition experiments for the control strain carrying IS5-Zn-gfp-prob under different temporal patterns of zinc availability. The Erm resistance remained low regardless of the life cycle. Data are presented as mean ± s.d. from 3 independent experiments.

Source data

Extended Data Fig. 7 Control experiments for coordinated lifestyle transition and amylase synthesis.

a-b, Quantification of the biofilm thickness and amylase activity of the amylase-encoding strain, which carries the plasmid IS5-Zn-amy-prob in the constant presence (a) and absence (b) of zinc. c-f, Quantification of the biofilm thickness and amylase activity of the strain carrying the plasmid P45-Zn-amy in four different zinc-changing environments. Experimental data are presented as mean ± s.d. from 3 independent experiments.

Source data

Extended Data Fig. 8 Control experiments for coordinated lifestyle transition and mHO-1 synthesis.

a-b, Quantification of the biofilm thickness and mHO-1 concentration of the mHO-1-encoding strain, which carries the plasmid IS5-Zn-mHO-1-prob in the constant presence (a) and absence (b) of zinc. c-f, Quantification of the biofilm thickness and mHO-1 concentration of the strain carrying the plasmid P45-Zn-mHO-1 in four different zinc-changing environments. Experimental data are presented as mean ± s.d. from 3 independent experiments.

Source data

Extended Data Fig. 9 Application of the lifestyle program for phase-specific, intracellular enzyme production.

a, Design of a gene circuit (IS5-Zn-gusA-prob) for GusA production by leveraging the modular structure in Fig. 5a. Here, the functional gene is gusA, which encodes beta-glucuronidase that converts p-nitrophenyl-β-D-glucopyranoside (PNPG) into the products, glucuronic acid and para-nitrophenol (PNP). PNP can be quantitatively measured by spectrometry at 420 nm. Compared to the functional molecules demonstrated in Fig. 5, one key difference here is that GusA remains intracellular and is not secreted to extracellular milieu. b-e, Quantification of the biofilm thickness and GusA activity of the strain carrying the plasmid IS5-Zn-gusA-prob in different zinc-changing environments. Notably, in response to zinc variations, cellular phase transitioned between the planktonic and biofilm states owing to the coordinated expression of IS5 and Protease B. However, there was no obvious reduction of GusA activity due to its high stability in the cell. f, Gene circuit for the plasmid P45-Zn-gusA. g-j, Quantification of the biofilm thickness and GusA activity of the strain carrying the plasmid P45-Zn-gusA in different zinc-changing environments. Neither biofilm decomposition nor GusA reduction was observed for this construct due to the lack of active degradation of P45 and GusA. Experimental data are presented as mean ± s.d. from 3 independent experiments.

Source data

Extended Data Fig. 10 Optimization of phase-specific control of intracellular GusA via engineered fast degradation.

a, Gene circuit for the optimized system, IS5-Zn-gusA-tag-prob-Pcst-lon, which contains an orthogonal protein degradation system (mf-Ion) and a degradation tag for GusA (gusA/tag). When zinc is present, IS5 expression is suppressed but Protease B is actively produced and secreted to disperse existing IS5 biofilm. Meanwhile, gusA is actively expressed with a fast degradation tag that can be recognized by the protease Mf-lon. In this case, the cell is in the planktonic state with a high level of tagged GusA. When zinc is absent, IS5 expression is turned on while the synthesis of Protease B is shut off, leading to biofilm formation. Meanwhile, the production of new GusA molecules is suppressed but the protease Mf-lon continues to actively digest existing tagged GusA, resulting in reduction of intracellular GusA concentration. The gene mf-lon is under the control of the low pH inducible promoter Pcst which is only active in the stationary phase, which reduces metabolic load and avoids excessive digestion of GusA when zinc is present. b-e, Quantification of the biofilm thickness and GusA activity of the strain carrying the plasmid IS5-Zn-gusA-tag-prob-Pcst-lon in different zinc-changing environments. With the optimized system, both cellular phase and GusA bioactivity showed clear transitions in response to environmental zinc availability. Experimental data are presented as mean ± s.d. from 3 independent experiments.

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Supplementary Figs. 1–3, Tables 1–3 and Refs. 1–6.

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Kong, W., Qian, Y., Stewart, P.S. et al. De novo engineering of a bacterial lifestyle program. Nat Chem Biol (2022). https://doi.org/10.1038/s41589-022-01194-1

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