{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:57:28Z","timestamp":1787029048513,"version":"build-2736575974"},"reference-count":36,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2020,7,7]],"date-time":"2020-07-07T00:00:00Z","timestamp":1594080000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000923","name":"Australian Research Council","doi-asserted-by":"publisher","award":["DP180100845"],"award-info":[{"award-number":["DP180100845"]}],"id":[{"id":"10.13039\/501100000923","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The Pseudomonas quinolone system (PQS) is one of the three major interconnected quorum sensing signaling systems in Pseudomonas aeruginosa. The virulence factors PQS and HHQ activate the transcription regulator PqsR (MvfR), which controls several activities in bacteria, including biofilm formation and upregulation of PQS biosynthesis. The enzyme anthraniloyl-CoA synthetase (PqsA) catalyzes the first and critical step in the biosynthesis of quinolones; therefore, it is an attractive target for the development of anti-virulence therapeutics against Pseudomonas resistance. Herein, we report the design and synthesis of novel triazole nucleoside-based anthraniloyl- adenosine monophosphate (AMP) mimics. These analogues had a major impact on the morphology of bacterial biofilms and caused significant reduction in bacterial aggregation and population density. However, the compounds showed only limited inhibition of PQS and did not exhibit any effect on pyocyanin production.<\/jats:p>","DOI":"10.3390\/molecules25133103","type":"journal-article","created":{"date-parts":[[2020,7,10]],"date-time":"2020-07-10T09:45:31Z","timestamp":1594374331000},"page":"3103","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Design, Synthesis and Biological Evaluation of Novel Anthraniloyl-AMP Mimics as PQS Biosynthesis Inhibitors Against Pseudomonas aeruginosa Resistance"],"prefix":"10.3390","volume":"25","author":[{"given":"Shekh","family":"Sabir","sequence":"first","affiliation":[{"name":"School of Chemistry, Faculty of Science, The University of New South Wales, Sydney, NSW 2052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4048-0630","authenticated-orcid":false,"given":"Sujatha","family":"Subramoni","sequence":"additional","affiliation":[{"name":"Singapore Centre for Environmental Life Sciences Engineering (SCELSE), Nanyang Technological University, Singapore 637551, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theerthankar","family":"Das","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Immunology, School of Medical Sciences, The University of Sydney, Sydney, NSW 2006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9300-4737","authenticated-orcid":false,"given":"David StC.","family":"Black","sequence":"additional","affiliation":[{"name":"School of Chemistry, Faculty of Science, The University of New South Wales, Sydney, NSW 2052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott A.","family":"Rice","sequence":"additional","affiliation":[{"name":"Singapore Centre for Environmental Life Sciences Engineering (SCELSE), Nanyang Technological University, Singapore 637551, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naresh","family":"Kumar","sequence":"additional","affiliation":[{"name":"School of Chemistry, Faculty of Science, The University of New South Wales, Sydney, NSW 2052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,7,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1038\/s41579-018-0125-x","article-title":"The cost of antimicrobial resistance","volume":"17","author":"Hofer","year":"2019","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1080\/17441692.2017.1336248","article-title":"Understanding media publics and the antimicrobial resistance crisis","volume":"13","author":"Davis","year":"2018","journal-title":"Glob. Public Health"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"76","DOI":"10.4103\/jms.jms_25_17","article-title":"World health organization releases global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics","volume":"32","author":"Shrivastava","year":"2018","journal-title":"J. Med. Soc."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.mib.2017.10.028","article-title":"Global antimicrobial resistance in Gram-negative pathogens and clinical need","volume":"39","author":"Theuretzbacher","year":"2017","journal-title":"Curr. Opin. Microbiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1016\/j.jhin.2009.04.020","article-title":"Pseudomonas aeruginosa: A formidable and ever-present adversary","volume":"73","author":"Kerr","year":"2009","journal-title":"J. Hosp. Infect."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/j.tim.2011.04.005","article-title":"Pseudomonas aeruginosa: All roads lead to resistance","volume":"19","author":"Breidenstein","year":"2011","journal-title":"Trends Microbiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1111\/j.1574-695X.2010.00690.x","article-title":"An update on Pseudomonas aeruginosa biofilm formation, tolerance, and dispersal","volume":"59","author":"Harmsen","year":"2010","journal-title":"FEMS Immunol. Med. Microbiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/S1473-3099(17)30753-3","article-title":"Discovery, research, and development of new antibiotics: The WHO priority list of antibiotic-resistant bacteria and tuberculosis","volume":"18","author":"Tacconelli","year":"2018","journal-title":"Lancet Infect. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1002\/phar.1868","article-title":"Past, present, and future of antibacterial economics: Increasing bacterial resistance, limited antibiotic pipeline, and societal implications","volume":"37","author":"Luepke","year":"2017","journal-title":"Pharmacother. J. Hum. Pharmacol. Drug Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1146\/annurev.cellbio.21.012704.131001","article-title":"QUORUM SENSING: Cell-to-Cell Communication in Bacteria","volume":"21","author":"Waters","year":"2005","journal-title":"Annu. Rev. Cell. Dev. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1111\/j.1574-6976.2001.tb00583.x","article-title":"Quorum-sensing in Gram-negative bacteria","volume":"25","author":"Whitehead","year":"2001","journal-title":"FEMS Microbiol. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1146\/annurev.micro.55.1.165","article-title":"Quorum sensing in bacteria","volume":"55","author":"Miller","year":"2001","journal-title":"Annu. Rev. Microbiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1080\/13543776.2018.1541174","article-title":"Quorum sensing inhibitors: A patent review (2014\u20132018)","volume":"28","author":"Chen","year":"2018","journal-title":"Expert Opin. Ther. Pat."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1432","DOI":"10.1039\/b703021p","article-title":"Expanding dialogues: From natural autoinducers to non-natural analogues that modulate quorum sensing in Gram-negative bacteria","volume":"37","author":"Geske","year":"2008","journal-title":"Chem. Soc. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"12762","DOI":"10.1021\/ja0530321","article-title":"Small molecule inhibitors of bacterial quorum sensing and biofilm formation","volume":"127","author":"Geske","year":"2005","journal-title":"J. Am. Chem. Soc."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"10385","DOI":"10.1021\/acs.jmedchem.8b00540","article-title":"Pseudomonas aeruginosa Quorum Sensing Systems as Drug Discovery Targets: Current Position and Future Perspectives","volume":"61","author":"Soukarieh","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1038\/nrmicro.2016.89","article-title":"Quorum sensing signal\u2013response systems in Gram-negative bacteria","volume":"14","author":"Papenfort","year":"2016","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1146\/annurev.genet.35.102401.090913","article-title":"Regulation of gene expression by cell-to-cell communication: Acyl-homoserine lactone quorum sensing","volume":"35","author":"Fuqua","year":"2001","journal-title":"Annu. Rev. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"444","DOI":"10.3389\/fcimb.2018.00444","article-title":"Interference with quorum-sensing signal biosynthesis as a promising therapeutic strategy against multidrug-resistant pathogens","volume":"8","author":"Rigueiras","year":"2019","journal-title":"Front. Cell Infect. Microbiol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Ib\u00e1\u00f1ez de Aldecoa, A.L., Zafra, O., and Gonz\u00e1lez-Pastor, J.E. (2017). Mechanisms and Regulation of Extracellular DNA Release and Its Biological Roles in Microbial Communities. Front. Microbiol., 8.","DOI":"10.3389\/fmicb.2017.01390"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Das, T., and Manefield, M. (2012). Pyocyanin promotes extracellular DNA release in Pseudomonas aeruginosa. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0046718"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Kang, D., Turner, K.E., and Kirienko, N.V. (2018). PqsA promotes pyoverdine production via biofilm formation. Pathogens, 7.","DOI":"10.3390\/pathogens7010003"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Lesic, B., L\u00e9pine, F., D\u00e9ziel, E., Zhang, J., Zhang, Q., Padfield, K., Castonguay, M.-H., Milot, S., Stachel, S., and Tzika, A.A. (2007). Inhibitors of pathogen intercellular signals as selective anti-infective compounds. PLoS Pathog., 3.","DOI":"10.1371\/journal.ppat.0030126"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.chembiol.2006.11.014","article-title":"The Pseudomonas aeruginosa 4-quinolone signal molecules HHQ and PQS play multifunctional roles in quorum sensing and iron entrapment","volume":"14","author":"Diggle","year":"2007","journal-title":"Chem. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4372","DOI":"10.1128\/JB.187.13.4372-4380.2005","article-title":"Regulation of Pseudomonas quinolone signal synthesis in Pseudomonas aeruginosa","volume":"187","author":"Wade","year":"2005","journal-title":"J. Bacteriol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3061","DOI":"10.1021\/acschembio.6b00575","article-title":"Designed small-molecule inhibitors of the anthranilyl-CoA synthetase PqsA block quinolone biosynthesis in Pseudomonas aeruginosa","volume":"11","author":"Ji","year":"2016","journal-title":"ACS Chem. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2045","DOI":"10.1002\/cbic.201700374","article-title":"Structures of the N-Terminal Domain of PqsA in Complex with Anthraniloyl-and 6-Fluoroanthraniloyl-AMP: Substrate Activation in Pseudomonas Quinolone Signal (PQS) Biosynthesis","volume":"18","author":"Witzgall","year":"2017","journal-title":"ChemBioChem"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1038\/nrd4010","article-title":"Advances in the development of nucleoside and nucleotide analogues for cancer and viral diseases","volume":"12","author":"Jordheim","year":"2013","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1002\/ajoc.201700260","article-title":"Synthesis of Amide-Linked Cyclic Dinucleotide Analogues with Pyrimidine Bases","volume":"6","author":"Pal","year":"2017","journal-title":"Asian J. Org. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1039\/C4CC07538B","article-title":"Supramolecular assemblies of novel aminonucleoside phospholipids and their bonding to nucleic acids","volume":"51","author":"Pan","year":"2015","journal-title":"Chem. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1002\/cmdc.201200060","article-title":"Synthesis of small molecules targeting multiple DNA structures using click chemistry","volume":"7","author":"Howell","year":"2012","journal-title":"ChemMedChem"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1081\/SCC-120017200","article-title":"An improved transient method for the synthesis of N-benzoylated nucleosides","volume":"33","author":"Zhu","year":"2003","journal-title":"Synth. Commun."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"443","DOI":"10.3389\/fcimb.2018.00443","article-title":"Itaconimides as novel quorum sensing inhibitors of Pseudomonas aeruginosa","volume":"8","author":"Fong","year":"2019","journal-title":"Front. Cell Infect. Microbiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e00102-19","DOI":"10.1128\/mSphere.00102-19","article-title":"Loss of the Two-Component System TctD-TctE in Pseudomonas aeruginosa Affects Biofilm Formation and Aminoglycoside Susceptibility in Response to Citric Acid","volume":"4","author":"Taylor","year":"2019","journal-title":"mSphere"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1318","DOI":"10.1099\/mic.0.2006\/004911-0","article-title":"Effects of iron on DNA release and biofilm development by Pseudomonas aeruginosa","volume":"153","author":"Yang","year":"2007","journal-title":"Microbiology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2000","DOI":"10.3389\/fmicb.2019.02000","article-title":"Conditions Under Which Glutathione Disrupts the Biofilms and Improves Antibiotic Efficacy of Both ESKAPE and Non-ESKAPE Species","volume":"10","author":"Das","year":"2019","journal-title":"Front. Microbiol."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/13\/3103\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:48:41Z","timestamp":1760176121000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/13\/3103"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,7]]},"references-count":36,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2020,7]]}},"alternative-id":["molecules25133103"],"URL":"https:\/\/doi.org\/10.3390\/molecules25133103","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,7,7]]}}}