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Previous studies have shown that Mg\n                    <jats:sup>2+<\/jats:sup>\n                    \u2009depletion enables\n                    <jats:italic>Pseudomonas aeruginosa<\/jats:italic>\n                    to become resistant to colistin. Here, we show that magnesium sequestration by\n                    <jats:italic>Candida albicans<\/jats:italic>\n                    also enables\n                    <jats:italic>P. aeruginosa<\/jats:italic>\n                    to evolve a nearly hundredfold higher level of colistin resistance through genetic changes in lipid A biosynthesis-modification pathways and a putative magnesium transporter. These mutations synergize with the Mg\n                    <jats:sup>2+<\/jats:sup>\n                    -sensing PhoPQ two-component signaling system to remodel lipid A structures of the bacterial outer membrane in previously uncharacterized ways. One predominant mutational pathway involves early mutations in\n                    <jats:italic>htrB2<\/jats:italic>\n                    , a non-essential gene involved in lipid A biosynthesis, which enhances resistance but compromises outer membrane integrity, resulting in fitness costs and increased susceptibility to other antibiotics. A second pathway achieves increased colistin resistance independently of\n                    <jats:italic>htrB2<\/jats:italic>\n                    mutations without compromising membrane integrity. In both cases, reduced colistin binding to the bacterial membrane underlies resistance. Our findings reveal that Mg\n                    <jats:sup>2+<\/jats:sup>\n                    scarcity triggers novel evolutionary trajectories, leading to extremely high colistin resistance in\n                    <jats:italic>P. aeruginosa<\/jats:italic>\n                    .\n                  <\/jats:p>","DOI":"10.1371\/journal.pbio.3003673","type":"journal-article","created":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T18:31:11Z","timestamp":1772562671000},"page":"e3003673","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["Magnesium depletion by Candida albicans unleashes two unusual modes of colistin resistance in Pseudomonas aeruginosa with different fitness costs"],"prefix":"10.1371","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8500-3873","authenticated-orcid":true,"given":"Yu-Ying 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