{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T15:34:54Z","timestamp":1787240094168,"version":"build-2736575974"},"reference-count":73,"publisher":"National Academy of Sciences","issue":"27","license":[{"start":{"date-parts":[[2023,6,26]],"date-time":"2023-06-26T00:00:00Z","timestamp":1687737600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"MOST | National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["22022401"],"award-info":[{"award-number":["22022401"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"MOST | National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["22074022"],"award-info":[{"award-number":["22074022"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"MOST | National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["21934001"],"award-info":[{"award-number":["21934001"]}],"id":[{"id":"10.13039\/501100001809","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":[[2023,7,4]]},"abstract":"<jats:p>\n                    Bacterial antimicrobial resistance (AMR) is among the most significant challenges to current human society. Exposing bacteria to antibiotics can activate their self-saving responses, e.g., filamentation, leading to the development of bacterial AMR. Understanding the molecular changes during the self-saving responses can reveal new inhibition methods of drug-resistant bacteria. Herein, we used an online microfluidics mass spectrometry system for real-time characterization of metabolic changes of bacteria during filamentation under the stimulus of antibiotics. Significant pathways, e.g., nucleotide metabolism and coenzyme A biosynthesis, correlated to the filamentation of extended-spectrum beta-lactamase-producing\n                    <jats:italic>Escherichia coli<\/jats:italic>\n                    (ESBL-\n                    <jats:italic>E. coli<\/jats:italic>\n                    ) were identified. A cyclic dinucleotide, c-di-GMP, which is derived from nucleotide metabolism and reported closely related to bacterial resistance and tolerance, was observed significantly up-regulated during the bacterial filamentation. By using a chemical inhibitor, ebselen, to inhibit diguanylate cyclases which catalyzes the synthesis of c-di-GMP, the minimum inhibitory concentration of ceftriaxone against ESBL-\n                    <jats:italic>E. coli<\/jats:italic>\n                    was significantly decreased. This inhibitory effect was also verified with other ESBL-\n                    <jats:italic>E. coli<\/jats:italic>\n                    strains and other beta-lactam antibiotics, i.e., ampicillin. A mutant strain of ESBL-\n                    <jats:italic>E. coli<\/jats:italic>\n                    by knocking out the\n                    <jats:italic>dgcM<\/jats:italic>\n                    gene was used to demonstrate that the inhibition of the antibiotic resistance to beta-lactams by ebselen was mediated through the inhibition of the diguanylate cyclase DgcM and the modulation of c-di-GMP levels. Our study uncovers the molecular changes during bacterial filamentation and proposes a method to inhibit antibiotic-resistant bacteria by combining traditional antibiotics and chemical inhibitors against the enzymes involved in bacterial self-saving responses.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2301170120","type":"journal-article","created":{"date-parts":[[2023,6,26]],"date-time":"2023-06-26T15:09:49Z","timestamp":1687792189000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":22,"title":["Molecular responses during bacterial filamentation reveal inhibition methods of drug-resistant bacteria"],"prefix":"10.1073","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8168-6264","authenticated-orcid":false,"given":"Dongxue","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Chemistry, Shanghai Stomatological Hospital, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Shanghai Stomatological Hospital, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qin","family":"Qin","sequence":"additional","affiliation":[{"name":"Changhai Hospital, The Naval Military Medical University, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6233-8459","authenticated-orcid":false,"given":"Liang","family":"Qiao","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Shanghai Stomatological Hospital, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2023,6,26]]},"reference":[{"key":"e_1_3_4_1_2","first-page":"63","article-title":"Antibiotic resistance in bacteria - an emerging public health problem","volume":"15","author":"Komolafe O. 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Zhang L. Qiao Molecular responses during bacterial filamentation induced by antibiotics. iProX. https:\/\/www.iprox.cn\/page\/project.html?id=IPX0005704000. 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