{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T01:08:24Z","timestamp":1789261704244,"version":"build-2803163510"},"reference-count":58,"publisher":"National Academy of Sciences","issue":"41","license":[{"start":{"date-parts":[[2023,10,5]],"date-time":"2023-10-05T00:00:00Z","timestamp":1696464000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"UKRI | Medical Research Council","doi-asserted-by":"publisher","award":["MR\/S009280\/1"],"award-info":[{"award-number":["MR\/S009280\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["104110\/Z\/14\/A"],"award-info":[{"award-number":["104110\/Z\/14\/A"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"UKRI | Medical Research Council","doi-asserted-by":"publisher","award":["MR\/M501608\/1"],"award-info":[{"award-number":["MR\/M501608\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"UKRI | Medical Research Council","doi-asserted-by":"publisher","award":["MR\/L015080\/1"],"award-info":[{"award-number":["MR\/L015080\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,10,10]]},"abstract":"<jats:p>\n                    <jats:italic>Streptococcus pneumoniae<\/jats:italic>\n                    is a major human pathogen and rising resistance to \u03b2-lactam antibiotics, such as penicillin, is a significant threat to global public health. Mutations occurring in the penicillin-binding proteins (PBPs) can confer high-level penicillin resistance but other poorly understood genetic factors are also important. Here, we combined strictly controlled laboratory experiments and population analyses to identify a new penicillin resistance pathway that is independent of PBP modification. Initial laboratory selection experiments identified high-frequency\n                    <jats:italic>pde1<\/jats:italic>\n                    mutations conferring\n                    <jats:italic>S. pneumoniae<\/jats:italic>\n                    penicillin resistance. The importance of variation at the\n                    <jats:italic>pde1<\/jats:italic>\n                    locus was confirmed in natural and clinical populations in an analysis of &gt;7,200\n                    <jats:italic>S. pneumoniae<\/jats:italic>\n                    genomes. The\n                    <jats:italic>pde1<\/jats:italic>\n                    mutations identified by these approaches reduce the hydrolytic activity of the Pde1 enzyme in bacterial cells and thereby elevate levels of cyclic-di-adenosine monophosphate and penicillin resistance. Our results reveal rapid de novo loss of function mutations in\n                    <jats:italic>pde1<\/jats:italic>\n                    as an evolutionary gateway conferring low-level penicillin resistance. This relatively simple genomic change allows cells to persist in populations on an adaptive evolutionary pathway to acquire further genetic changes and high-level penicillin resistance.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2308029120","type":"journal-article","created":{"date-parts":[[2023,10,5]],"date-time":"2023-10-05T13:58:08Z","timestamp":1696514288000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":29,"title":["Loss of Pde1 function acts as an evolutionary gateway to penicillin resistance in\n                    <i>Streptococcus pneumoniae<\/i>"],"prefix":"10.1073","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4393-5829","authenticated-orcid":false,"given":"Carolin M.","family":"Kobras","sequence":"first","affiliation":[{"name":"School for Biosciences, Florey Institute for Host-Pathogen Interactions, University of Sheffield, Sheffield S10 2TN, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7425-0001","authenticated-orcid":false,"given":"William","family":"Monteith","sequence":"additional","affiliation":[{"name":"Department of Biology, Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford OX1 3SZ, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0092-526X","authenticated-orcid":false,"given":"Sophie","family":"Somerville","sequence":"additional","affiliation":[{"name":"School for Biosciences, Florey Institute for Host-Pathogen Interactions, University of Sheffield, Sheffield S10 2TN, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James M.","family":"Delaney","sequence":"additional","affiliation":[{"name":"School for Biosciences, Florey Institute for Host-Pathogen Interactions, University of Sheffield, Sheffield S10 2TN, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5372-506X","authenticated-orcid":false,"given":"Imran","family":"Khan","sequence":"additional","affiliation":[{"name":"School for Biosciences, Florey Institute for Host-Pathogen Interactions, University of Sheffield, Sheffield S10 2TN, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6702-4428","authenticated-orcid":false,"given":"Camilla","family":"Brimble","sequence":"additional","affiliation":[{"name":"School for Biosciences, Florey Institute for Host-Pathogen Interactions, University of Sheffield, Sheffield S10 2TN, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6031-1148","authenticated-orcid":false,"given":"Rebecca M.","family":"Corrigan","sequence":"additional","affiliation":[{"name":"School for Biosciences, Florey Institute for Host-Pathogen Interactions, University of Sheffield, Sheffield S10 2TN, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6901-3203","authenticated-orcid":false,"given":"Samuel K.","family":"Sheppard","sequence":"additional","affiliation":[{"name":"Department of Biology, Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford OX1 3SZ, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4042-4580","authenticated-orcid":false,"given":"Andrew K.","family":"Fenton","sequence":"additional","affiliation":[{"name":"School for Biosciences, Florey Institute for Host-Pathogen Interactions, University of Sheffield, Sheffield S10 2TN, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2023,10,5]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(18)30310-4"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(22)02185-7"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(09)61114-4"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1136\/thx.2009.121434"},{"key":"e_1_3_4_5_2","volume-title":"Ampicillin., StatPearls [Internet]","author":"Peechakara B. 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Sommer , Mutations in the gdpP gene are a clinically relevant mechanism for \u03b2-lactam resistance in meticillin-resistant Staphylococcus aureus lacking mec determinants. Microb. Genom. 7, 000623 (2021).","journal-title":"Microb. 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