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Nat. Microbiol., Jan 16 2024, | https://doi.org/10.1038/s41564-023-01583-9 Engineered probiotic overcomes pathogen defences using signal interference and antibiotic production to treat infection in mice

Hackwon Do^1,2,3,11, Zhong-Rui Li^4,11, Praveen Kumar Tripathi^1,2,11, Sonali Mitra^1,2, Stephanie Guerra⁵, Ananya Dash ⁵, Dulanthi Weerasekera^1,2, Nishanth Makthal^1,2, Syed Shams^1,2, Shifu Aggarwal^1,2, Bharat Bhushan Singh^1,2, Di Gu ⁶, Yongle Du⁴, Randall J. Olsen^1,2,7, Christopher LaRock ^5,8,9, Wenjun Zhang^4,10& Muthiah Kumaraswami^1,2

¹Center for Molecular and Translational Human Infectious Diseases Research, Houston Methodist Research Institute, Houston, TX, USA.

²Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TX, USA.

³Research unit of cryogenic novel material, Korea Polar Research Institute, Incheon, South Korea.

⁴Department of Chemical and Biomolecular Engineering, University of California, Berkeley, CA, USA.

⁵Department of Microbiology and Immunology, Emory School of Medicine, Atlanta, GA, USA.

⁶Department of Chemistry, University of California, Berkeley, CA, USA.

⁷Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, NY, USA.

⁸Department of Medicine, Division of Infectious Diseases, Emory School of Medicine, Atlanta, GA, USA.

⁹Emory Antibiotic Resistance Center, Emory School of Medicine, Atlanta, GA, USA.

¹⁰Chan Zuckerberg Biohub, San Francisco, CA, USA.

¹¹These authors contributed equally: Hackwon Do, Zhong-Rui Li, Praveen Kumar Tripathi.

Corresponding authors : Correspondence to Wenjun Zhang or Muthiah Kumaraswami.

Abstract

Probiotic supplements are suggested to promote human health by preventing pathogen colonization. However, the mechanistic bases for their efficacy in vivo are largely uncharacterized. Here using metabolomics and bacterial genetics, we show that the human oral probiotic Streptococcus salivarius K12 (SAL) produces salivabactin, an antibiotic that effectively inhibits pathogenic Streptococcus pyogenes (GAS) in vitro and in mice. However, prophylactic dosing with SAL enhanced GAS colonization in mice and ex vivo in human saliva. We showed that, on co-colonization, GAS responds to a SAL intercellular peptide signal that controls SAL salivabactin production. GAS produces a secreted protease, SpeB, that targets SAL-derived salivaricins and enhances GAS survival. Using this knowledge, we re-engineered probiotic SAL to prevent signal eavesdropping by GAS and potentiate SAL antimicrobials. This engineered probiotic demonstrated superior efficacy in preventing GAS colonization in vivo. Our findings show that knowledge of interspecies interactions can identify antibiotic- and probiotic-based strategies to combat infection.

논문정보

형식Research article
게재일2024년 01월 (BRIC 등록일 2024-01-17)
연구진국내+국외 연구진
분야 생명과학 > 생화학

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