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Of particular concern is the emergence of multidrug-resistant strains, which has been rapid among Gram-negative bacteria such as<jats:italic>Escherichia coli<\/jats:italic>. A large body of work has established that antibiotic resistance mechanisms depend on phenotypic heterogeneity, which may be mediated by stochastic expression of antibiotic resistance genes. The link between such molecular-level expression and the population levels that result is complex and multi-scale. Therefore, to better understand antibiotic resistance, what is needed are new mechanistic models that reflect single-cell phenotypic dynamics together with population-level heterogeneity, as an integrated whole. In this work, we sought to bridge single-cell and population-scale modeling by building upon our previous experience in \u201cwhole-cell\u201d modeling, an approach which integrates mathematical and mechanistic descriptions of biological processes to recapitulate the experimentally observed behaviors of entire cells. To extend whole-cell modeling to the \u201cwhole-colony\u201d scale, we embedded multiple instances of a whole-cell<jats:italic>E<\/jats:italic>.<jats:italic>coli<\/jats:italic>model within a model of a dynamic spatial environment, allowing us to run large, parallelized simulations on the cloud that contained all the molecular detail of the previous whole-cell model and many interactive effects of a colony growing in a shared environment. The resulting simulations were used to explore the response of<jats:italic>E<\/jats:italic>.<jats:italic>coli<\/jats:italic>to two antibiotics with different mechanisms of action, tetracycline and ampicillin, enabling us to identify sub-generationally-expressed genes, such as the beta-lactamase ampC, which contributed greatly to dramatic cellular differences in steady-state periplasmic ampicillin and was a significant factor in determining cell survival.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1011232","type":"journal-article","created":{"date-parts":[[2023,6,16]],"date-time":"2023-06-16T17:30:53Z","timestamp":1686936653000},"page":"e1011232","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":14,"title":["Whole-cell modeling of E. coli colonies enables quantification of single-cell heterogeneity in antibiotic responses"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6344-7331","authenticated-orcid":true,"given":"Christopher J.","family":"Skalnik","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean Y.","family":"Cheah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mica Y.","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mattheus B.","family":"Wolff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6080-3142","authenticated-orcid":true,"given":"Ryan 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