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We previously demonstrated that\n                      <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                      can become resistant to growth-inhibitory compounds during experimental evolution. While resistance arose rapidly, the underlying mechanisms were not obvious as only a few genetic mutations were associated with resistance, while ample phenotypic changes occurred. We thus hypothesize that resistance may result from a combination of phenotypic responses and genetic adaptation. Here, we tested this hypothesis using proteomics. We first focused on an evolved strain that acquired a single mutation in\n                      <jats:italic toggle=\"yes\">tcyA<\/jats:italic>\n                      (encoding a transmembrane transporter unit) upon exposure to\n                      <jats:italic toggle=\"yes\">P. aeruginosa<\/jats:italic>\n                      supernatant. We show that this mutation leads to a complete abolishment of transporter synthesis, which confers moderate protection against\n                      <jats:italic toggle=\"yes\">Pseudomonas<\/jats:italic>\n                      quinolone signal and selenocystine, two toxic compounds produced by\n                      <jats:italic toggle=\"yes\">P. aeruginosa<\/jats:italic>\n                      . However, this genetic effect was minor compared to the fundamental phenotypic changes observed at the proteome level when both ancestral and evolved\n                      <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                      strains were exposed to\n                      <jats:italic toggle=\"yes\">P. aeruginosa<\/jats:italic>\n                      supernatant. Major changes involved the downregulation of virulence factors, metabolic pathways, and membrane transporters, and the upregulation of reactive oxygen species scavengers and an efflux pump. Our results suggest that the observed multivariate phenotypic response is a powerful adaptive strategy, offering instant protection against competitors in fluctuating environments and reducing the need for hard-wired genetic adaptations.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        Different bacterial pathogens can co-occur in infections, where they interact with one another and influence disease severity. Previous research showed that pathogens can evolve and adapt to co-infecting species. Here, we show that evolution through genetic mutations and selection is not necessarily required to change pathogen behavior. Instead, we found that the human pathogen\n                        <jats:italic toggle=\"yes\">Staphylococcus aureus<\/jats:italic>\n                        is able to plastically respond to the presence of\n                        <jats:italic toggle=\"yes\">Pseudomonas aeruginosa<\/jats:italic>\n                        , a competing pathogen. Through proteomics and metabolomics, we demonstrate that\n                        <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                        undergoes substantial proteomic alterations in response to\n                        <jats:italic toggle=\"yes\">P. aeruginosa<\/jats:italic>\n                        by downregulating virulence factor expression, changing metabolism, and mounting protective measures against toxic compounds. Our work highlights that pathogens possess sophisticated mechanisms to respond to competitors to secure growth and survival in polymicrobial infections. We predict such plastic responses to have significant impacts on infection outcomes.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/msystems.00262-25","type":"journal-article","created":{"date-parts":[[2025,7,31]],"date-time":"2025-07-31T11:06:36Z","timestamp":1753959996000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":2,"title":["A combination of phenotypic responses and genetic adaptations enables\n                    <i>Staphylococcus aureus<\/i>\n                    to withstand inhibitory molecules secreted by\n                    <i>Pseudomonas aeruginosa<\/i>"],"prefix":"10.1128","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2063-6404","authenticated-orcid":true,"given":"Lukas","family":"Schwyter","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02crff812","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Quantitative Biomedicine, University of Zurich","place":["Zurich, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Selina","family":"Niggli","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02crff812","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Quantitative Biomedicine, University of Zurich","place":["Zurich, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Zajac","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02crff812","id-type":"ROR","asserted-by":"publisher"}],"name":"Functional Genomics Center Zurich, ETH Zurich and University of Zurich","place":["Zurich, Switzerland"]},{"name":"Swiss Institute of Bioinformatics (SIB) Quartier Sorge - 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