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Outbreak strains of these pathogens often demonstrate a remarkable ability to establish infection and easily acquire novel antimicrobial resistance mechanisms. Because the expression of virulence factors and antimicrobial resistance genes often imposes a fitness cost, successful host-adapted strains must evolve without compromising their ability to colonize the niches found in the human body. The ongoing spread of these multidrug-resistant strains suggests that these bacterial pathogens are actively adapting to antibiotic-treated hosts. With whole-genome sequencing, we can now identify the multiple genetic changes associated with host adaptation and increased antibiotic resistance. Yet, pinpointing the specific mutations responsible for phenotypic shifts through sequencing of clinical isolates remains challenging due to the high mutational load accumulated during infection. For this reason, our understanding of how pathogens evolve within specific host niches, both in the presence and absence of antibiotics, remains limited. Experimental evolution within host tissues now allows us to more accurately simulate the conditions under which antibiotic resistance and pathoadaptations emerge. In this Perspective article, we evaluate some of the systems currently employed, discuss their respective advantages and limitations and introduce engineered human microtissue models as a promising platform for bacterial experimental evolution.<\/jats:p>","DOI":"10.1099\/mic.0.001767","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T16:17:50Z","timestamp":1789143470000},"source":"Crossref","is-referenced-by-count":1,"title":["Simulating the host niche: balancing complexity and control in the experimental evolution of antibiotic resistance and pathoadaptation"],"prefix":"10.1099","volume":"172","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6106-2438","authenticated-orcid":false,"given":"Juan","family":"Hernandez-Bird","sequence":"first","affiliation":[{"name":"Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA, USA"},{"name":"Department of Medicine, Harvard Medical School, Boston, MA, USA"},{"name":"Center for Integrated Solutions for Infectious Diseases, Broad Institute of Harvard and MIT, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3194-7136","authenticated-orcid":false,"given":"Lucas A","family":"Meirelles","sequence":"additional","affiliation":[{"name":"Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA, USA"},{"name":"Department of Medicine, Harvard Medical School, Boston, MA, USA"},{"name":"Center for Integrated Solutions for Infectious Diseases, Broad Institute of Harvard and MIT, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"345","reference":[{"key":"R1","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-024-01054-w"},{"key":"R2","article-title":"Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. 12th ed. 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s:\/\/www.microbiologyresearch.org\/content\/journal\/micro\/10.1099\/mic.0.001767?crawler=true&mimetype=application\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T11:16:35Z","timestamp":1789730195000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.microbiologyresearch.org\/content\/journal\/micro\/10.1099\/mic.0.001767"}},"subtitle":["&lt;xhtml:span xmlns:xhtml=\"http:\/\/www.w3.org\/1999\/xhtml\" xml:lang=\"en\"&gt;&lt;p&gt;This article is part of our &lt;span style=\"color: rgb(33, 51, 104);\"&gt;&lt;a href=\"\/content\/emerging-investigators-collection-2025-26\"&gt;Emerging Investigators collection&lt;\/a&gt;&lt;\/span&gt;.&lt;\/p&gt;&lt;p style=\"line-height: 1.2;\"&gt;&lt;img src=\"\/upload\/emerging\/Lucas_Merielles.png\" alt=\"photograph of Lucas Meirelles\" class=\"ImageBorder img-responsive eb-people fr-fic fr-dib\" style=\"width: 120px; float: left; margin: 0 10px 10px 0;\" \/&gt;&lt;span style=\"font-size: 12px; font-weight: normal;\"&gt;&lt;strong&gt;Lucas A. Meirelles&amp;#160;&lt;\/strong&gt;is a Principal Investigator at the Center for Computational and Integrative Biology at Massachusetts General Hospital, where his lab studies host-pathogen co-adaptation in chronic lung infections. Combining human microtissues and organoids with imaging and omics, the lab investigates how bacteria grow and survive antibiotics in the airway and how these pathogens affect epithelial regeneration following damage. Lucas is also a Faculty of Medicine at Harvard Medical School, an Associate Member of the Broad Institute, and an investigator in the Center for Integrated Solutions for Infectious Diseases. Originally from Brazil, Lucas began his scientific journey studying social insects and their microbial parasites at S\u00e3o Paulo State University and the UT Austin. He earned his PhD at Caltech with Dianne Newman, studying the physiological roles of redox-active metabolites secreted by bacteria, and completed postdoctoral work with Alex Persat at EPFL, studying &lt;em&gt;Pseudomonas aeruginosa&lt;\/em&gt; adaptation to the airway mucosa.&amp;#160;&lt;\/span&gt;&lt;\/p&gt;\n&lt;\/xhtml:span&gt;"],"short-title":[],"issued":{"date-parts":[[2026,9,11]]},"references-count":131,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2026,9,11]]}},"URL":"https:\/\/doi.org\/10.1099\/mic.0.001767","relation":{},"ISSN":["1350-0872","1465-2080"],"issn-type":[{"value":"1350-0872","type":"print"},{"value":"1465-2080","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,11]]}}}