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Understanding what determines evolvability differences is of great interest from both fundamental and applied perspectives. A general pattern observed across multiple microbes is that evolvability tends to decline with genotype fitness (\n                    <jats:italic>i.e.<\/jats:italic>\n                    , the \u201crule of declining adaptability\u201d), typically attributed to epistatic rather than mutational differences among genotypes. Here, we investigate whether common\n                    <jats:italic>rpsL<\/jats:italic>\n                    point mutations in\n                    <jats:italic>Escherichia coli<\/jats:italic>\n                    , conferring streptomycin resistance, may potentiate or hinder adaptation towards secondary aminoglycosides. We find a version of the rule of declining adaptability in which initially more-fit genotypes experience higher effective beneficial mutation rates but smaller effect sizes than their less-fit counterparts. Genome sequencing reveals the ribosome and electron transport chain as primary targets for adaptation. Second-step mutations typically confer cross-resistance across aminoglycosides, and some even restore fitness costs in the absence of drugs. However, some genotypes deviate markedly from the overall pattern, being completely unable to develop resistance to the secondary aminoglycosides. Such idiosyncratic dead-ends, if common among other systems involving single-point mutants, would expand the pool of potential targets for strategies to promote evolutionary robustness in biotechnology and combat multidrug resistance in clinical microbiology.\n                  <\/jats:p>","DOI":"10.1371\/journal.pgen.1011832","type":"journal-article","created":{"date-parts":[[2025,8,25]],"date-time":"2025-08-25T17:35:20Z","timestamp":1756143320000},"page":"e1011832","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["Idiosyncratic evolvability among single-point ribosomal mutants towards multi-aminoglycoside resistance"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1511-492X","authenticated-orcid":true,"given":"Laura","family":"S\u00e1nchez-Maroto","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guillem 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