{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T18:19:49Z","timestamp":1787941189946,"version":"build-2784847793"},"update-to":[{"DOI":"10.1371\/journal.ppat.1014537","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T00:00:00Z","timestamp":1787875200000}}],"reference-count":86,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T00:00:00Z","timestamp":1787529600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82372298, 32170160"],"award-info":[{"award-number":["82372298, 32170160"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32400017"],"award-info":[{"award-number":["32400017"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100018537","name":"National Science and Technology Major Project","doi-asserted-by":"publisher","award":["2024ZD0532700"],"award-info":[{"award-number":["2024ZD0532700"]}],"id":[{"id":"10.13039\/501100018537","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100018537","name":"National Science and Technology Major Project","doi-asserted-by":"publisher","award":["2024ZD0532804"],"award-info":[{"award-number":["2024ZD0532804"]}],"id":[{"id":"10.13039\/501100018537","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010877","name":"Science, Technology and Innovation Commission of Shenzhen Municipality","doi-asserted-by":"publisher","award":["JCYJ20241202124801003"],"award-info":[{"award-number":["JCYJ20241202124801003"]}],"id":[{"id":"10.13039\/501100010877","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2024M750589"],"award-info":[{"award-number":["2024M750589"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    The integration of environmental cues to counter selective pressures is crucial for the epidemiological success of major human pathogens.\n                    <jats:italic>Klebsiella pneumoniae<\/jats:italic>\n                    poses an increasing critical public health threat due to its high biofilm forming capacity and adaptive antimicrobial resistance. While the second messenger cyclic di-GMP (c-di-GMP) is a key regulator of bacterial cellular physiological adaptations, its downstream effectors that control antibiotic resistance remain unknown in\n                    <jats:italic>K. pneumoniae.<\/jats:italic>\n                    Unlike c-di-GMP metabolizing enzymes, which contain highly conserved GGDEF or EAL domains, effectors enable signal transduction through structurally heterogeneous sensing domains that defy homology-based prediction. Here, we identified that upon the elevation of intracellular c-di-GMP levels induced by antibiotic treatmen,\u00a0the universal stress protein UspG (AVR78_17055) serves as a cryptic, direct c-di-GMP effector in extended-spectrum beta-lactamase (ESBL)-producing strain\n                    <jats:italic>K. quasipneumoniae<\/jats:italic>\n                    ATCC 700603. Utilizing site-directed mutagenesis and EMSA, we demonstrate that UspG senses elevated intracellular c-di-GMP levels, thereby promoting biofilm formation, via N39 and K116 residues. Mechanistically, c-di-GMP binding enhances the binding affinity of UspG to the transcriptional repressor RamR. This specific protein sequestration antagonizes RamR, a transcriptional repressor that regulates RamA expression, thereby derepressing the\n                    <jats:italic>ramA<\/jats:italic>\n                    locus and unleashing a regulatory program that fortifies lipid A biosynthesis, upregulates multidrug efflux pumps expression, and promotes biofilm development. Importantly, this c-di-GMP\u2013UspG axis is not restricted to ESBL-producing lineages. Through mutagenesis verification, we discovered similar phenotypic dependency in hypervirulent\n                    <jats:italic>K. pneumoniae<\/jats:italic>\n                    ATCC 43816. These findings indicate that UspG is functionally conserved across\n                    <jats:italic>Enterobacteriaceae<\/jats:italic>\n                    . By elucidating how\n                    <jats:italic>Klebsiella<\/jats:italic>\n                    exploits UspG to bridge intracellular nucleotide signaling with acute environmental adaptation, our study provides a new therapeutic target for recalcitrant\n                    <jats:italic>Klebsiella<\/jats:italic>\n                    infections.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1014537","type":"journal-article","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T17:39:25Z","timestamp":1787593165000},"page":"e1014537","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cyclic di-GMP directly reprograms the multidrug resistance machinery via UspG-mediated sequestration of RamR in Klebsiella"],"prefix":"10.1371","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9401-9770","authenticated-orcid":true,"given":"Xiaoxiao","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingfang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yikai","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangjie","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miao","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiwen","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunhu","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinyue","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,8,24]]},"reference":[{"key":"ppat.1014537.ref001","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1016\/S0140-6736(24)01867-1","article-title":"Global 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