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Although numerous drugs have been found to disrupt the health of the human microbiome, no comprehensive comparison between established drug targets and the human microbiome metaproteome has yet been conducted. Therefore, herein, sequence and structure alignments between human and pathogen drug targets and representative human gut, oral, and vaginal microbiome metaproteomes were performed. Both human and pathogen drug targets were found to be similar in sequence, function, structure, and drug binding capacity to proteins in diverse pathogenic and non-pathogenic bacteria from all three microbiomes. The gut metaproteome was identified as particularly susceptible overall to off-target effects. Certain symptoms, such as infections and immune disorders, may be more common among drugs that non-selectively target host microbiota. These findings suggest that similarities between human microbiome metaproteomes and drug target candidates should be routinely checked.<\/jats:p>","DOI":"10.1038\/s41397-025-00367-0","type":"journal-article","created":{"date-parts":[[2025,4,17]],"date-time":"2025-04-17T15:03:26Z","timestamp":1744902206000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Similarity of drug targets to human microbiome metaproteome promotes pharmacological promiscuity"],"prefix":"10.1038","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0232-0281","authenticated-orcid":false,"given":"Christopher A.","family":"Beaudoin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shannon","family":"Norget","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziad","family":"Omran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharif","family":"Hala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdullah H.","family":"Daqeeq","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip W. 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