TY - JOUR
T1 - Engineered probiotic overcomes pathogen defences using signal interference and antibiotic production to treat infection in mice
AU - Do, Hackwon
AU - Li, Zhong Rui
AU - Tripathi, Praveen Kumar
AU - Mitra, Sonali
AU - Guerra, Stephanie
AU - Dash, Ananya
AU - Weerasekera, Dulanthi
AU - Makthal, Nishanth
AU - Shams, Syed
AU - Aggarwal, Shifu
AU - Singh, Bharat Bhushan
AU - Gu, Di
AU - Du, Yongle
AU - Olsen, Randall J.
AU - LaRock, Christopher
AU - Zhang, Wenjun
AU - Kumaraswami, Muthiah
N1 - Funding Information:
The authors acknowledge the National Institutes of Health grants R01 AI146048 and 1R01AI162748 (M.K.); National Institutes of Health grant DP2AT009148 (W.Z.); Chan Zuckerberg Biohub Investigator Program (W.Z.); National Institutes of Health grant R01 AI153071 (C.L.); and Burroughs Wellcome Fund Investigators in the Pathogenesis of Infectious Diseases Award (C.L.).
Publisher Copyright:
© 2024, The Author(s).
PY - 2024/2
Y1 - 2024/2
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85182476308&partnerID=8YFLogxK
U2 - 10.1038/s41564-023-01583-9
DO - 10.1038/s41564-023-01583-9
M3 - Article
C2 - 38228859
AN - SCOPUS:85182476308
SN - 2058-5276
VL - 9
SP - 502
EP - 513
JO - Nature Microbiology
JF - Nature Microbiology
IS - 2
M1 - 9
ER -