{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T08:14:06Z","timestamp":1771488846701,"version":"3.50.1"},"posted":{"date-parts":[[2023,3,25]]},"group-title":"Microbiology","reference-count":75,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,9,19]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  The Resistance-Nodulation-Division (RND) efflux pump superfamily is pervasive among Gram-negative pathogens and contributes extensively to clinical antibiotic resistance. The opportunistic pathogen\n                  <jats:italic>Pseudomonas aeruginosa<\/jats:italic>\n                  contains 12 RND-type efflux systems, with four contributing to resistance including MexXY-OprM which is uniquely able to export aminoglycosides. At the site of initial substrate recognition, small molecule probes of the inner membrane transporter (e.g., MexY) have potential as important functional tools to understand substrate selectivity and a foundation for developing adjuvant efflux pump inhibitors (EPIs). Here, we optimized the scaffold of berberine, a known but weak MexY EPI, using an\n                  <jats:italic>in-silico<\/jats:italic>\n                  high-throughput screen to identify di-berberine conjugates with enhanced synergistic action with aminoglycosides. Further, docking and molecular dynamics simulations of di-berberine conjugates reveal unique contact residues and thus sensitivities of MexY from distinct\n                  <jats:italic>P. aeruginosa<\/jats:italic>\n                  strains. This work thereby reveals di-berberine conjugates to be useful probes of MexY transporter function and potential leads for EPI development.\n                <\/jats:p>","DOI":"10.1101\/2023.03.24.533986","type":"posted-content","created":{"date-parts":[[2023,3,25]],"date-time":"2023-03-25T19:35:16Z","timestamp":1679772916000},"source":"Crossref","is-referenced-by-count":3,"title":["Di-berberine conjugates as chemical probes of\n                  <i>Pseudomonas aeruginosa<\/i>\n                  MexXY-OprM efflux function and inhibition"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9467-7175","authenticated-orcid":false,"given":"Logan G.","family":"Kavanaugh","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew R.","family":"Mahoney","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0222-6092","authenticated-orcid":false,"given":"Debayan","family":"Dey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5198-7744","authenticated-orcid":false,"given":"William M.","family":"Wuest","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2419-380X","authenticated-orcid":false,"given":"Graeme L.","family":"Conn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2023092213100925000_2023.03.24.533986v3.1","unstructured":"Centers for Disease, C. & Prevention. Antibiotic Resistance Threats in the United States, 2019. (Centers for Disease Control and Prevention, 2019)."},{"key":"2023092213100925000_2023.03.24.533986v3.2","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(21)02724-0"},{"key":"2023092213100925000_2023.03.24.533986v3.3","doi-asserted-by":"crossref","unstructured":"Jurado-Mart\u00edn, I. , Sainz-Mej\u00edas, M. & McClean, S. Pseudomonas aeruginosa: An Audacious Pathogen with an Adaptable Arsenal of Virulence Factors. Int J Mol Sci 22(2021).","DOI":"10.3390\/ijms22063128"},{"key":"2023092213100925000_2023.03.24.533986v3.4","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-031-08491-1_13"},{"key":"2023092213100925000_2023.03.24.533986v3.5","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-021-01635-6"},{"key":"2023092213100925000_2023.03.24.533986v3.6","doi-asserted-by":"publisher","DOI":"10.2217\/fmb.14.66"},{"key":"2023092213100925000_2023.03.24.533986v3.7","doi-asserted-by":"crossref","unstructured":"Kishk, R.M. , et al. Efflux MexAB-Mediated Resistance in P. aeruginosa Isolated from Patients with Healthcare Associated Infections. 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