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Pathogen-specific antimicrobials engineered de novo through membrane-protein biomimicry

Abstract

Precision antimicrobials aim to kill pathogens without damaging commensal bacteria in the host, and thereby cure disease without antibiotic-associated dysbiosis. Here we report the de novo design of a synthetic host defence peptide that targets a specific pathogen by mimicking key molecular features of the pathogen’s channel-forming membrane proteins. By exploiting physical and structural vulnerabilities within the pathogen’s cellular envelope, we designed a peptide sequence that undergoes instructed tryptophan-zippered assembly within the mycolic acid-rich outer membrane of Mycobacterium tuberculosis to specifically kill the pathogen without collateral toxicity towards lung commensal bacteria or host tissue. These mycomembrane-templated assemblies elicit rapid mycobactericidal activity and enhance the potency of antibiotics by improving their otherwise poor diffusion across the rigid M. tuberculosis envelope with respect to agents that exploit transmembrane protein channels for antimycobacterial activity. This biomimetic strategy may aid the design of other narrow-spectrum antimicrobial peptides.

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Fig. 1: Biomimetic design and biophysical analysis of MAD1.
Fig. 2: Atomistic mechanisms of MAD1 assembly.
Fig. 3: Ex cellulo analysis of MAD1 mycobacterial-membrane specificity.
Fig. 4: In situ characterization of Mtb envelope disruption by MAD1.
Fig. 5: MAD1 polymicrobial selectivity and combinatorial synergy.

Data availability

The main data supporting the results in this study are available within the paper and its Supplementary Information. The raw and analysed datasets generated during the study are too large to be publicly shared, but they are available for research purposes from the corresponding author on reasonable request.

Code availability

The parallelized DMD simulation engine (πDMD, v.1.0) with Medusa all-atom force field is available from Molecules In Action (http://moleculesinaction.com). The software is available for free to academic users.

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Acknowledgements

We thank the Penn State Microscopy and Cytometry Facility, University Park, PA for assistance with confocal and electron microscopy; the Penn State X-Ray Crystallography Facility, University Park, PA for use of the CD spectrophotometer; the Penn State NMR Facility, University Park, PA for use of NMR instrumentation. Funding for this research was provided by the Penn State Institute of Energy and the Environment Human Health and the Environment Seed Grant awarded to S.H.M. This work was also supported by NIH grant number AI123146 to A.D.B. A.W.S. was supported by funds from the Penn State Graduate Research Fellowship.

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A.W.S. and S.H.M. conceived the hypothesis, designed the experiments and wrote the manuscript. A.W.S., A.S.M., M.R.A., J.N.A., D.C.C., A.L., M.D.H., A.B., T.K.M., C.G., A.E., A.D.B., E.A.P. and K.C.K. designed and performed the experiments, analysed the results and contributed to writing of the manuscript.

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Correspondence to Scott H. Medina.

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Simonson, A.W., Mongia, A.S., Aronson, M.R. et al. Pathogen-specific antimicrobials engineered de novo through membrane-protein biomimicry. Nat Biomed Eng (2021). https://doi.org/10.1038/s41551-020-00665-x

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