{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:45:53Z","timestamp":1792791953594,"version":"4.5.0"},"reference-count":63,"publisher":"American Society for Microbiology","issue":"4","license":[{"start":{"date-parts":[[2025,4,9]],"date-time":"2025-04-09T00:00:00Z","timestamp":1744156800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,4,9]],"date-time":"2025-04-09T00:00:00Z","timestamp":1744156800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"HHS | National Institutes of Health","award":["P01 AI083214"],"award-info":[{"award-number":["P01 AI083214"]}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2025,4,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      <jats:italic>Acinetobacter baumannii<\/jats:italic>\n                      is a high-priority organism for the development of new antibacterial treatments. We found that the antimalarial medication mefloquine (MFQ) permeabilized the bacterial cell membrane of\n                      <jats:italic>A. baumannii<\/jats:italic>\n                      , decreased membrane fluidity, and caused physical injury to the membrane. MFQ also maintained activity across different pH conditions (pH range: 5\u20138). Structure-activity relationship analysis using MFQ analogs demonstrated that piperidin-2-yl methanol is required for antibacterial activity. Scanning and transmission electron microscopy demonstrated the compromised morphological and membrane integrity in MFQ-treated cells. MFQ synergized with the membrane permeabilizers polymyxin B and colistin and the MFQ + polymyxin B combination killed bacterial cells more effectively than either treatment alone. MFQ + polymyxin B was effective against other gram-negative bacteria including\n                      <jats:italic>Escherichia coli<\/jats:italic>\n                      ,\n                      <jats:italic>Burkholderia pseudomallei<\/jats:italic>\n                      ,\n                      <jats:italic>Klebsiella pneumoniae<\/jats:italic>\n                      , and\n                      <jats:italic>Pseudomonas aeruginosa<\/jats:italic>\n                      . Bodipy-cadaverine displacement assays confirmed the active interaction of MFQ with other membrane lipid components, such as lipopolysaccharide, lipid A, lipoteichoic acids, and fatty acids. In all-atom molecular dynamics simulations, lipid interactions facilitated the permeation of MFQ into the simulated Gram-negative membrane. Additionally, positively charged nitrogen in the piperidine group of MFQ seems to enhance interactions with the negatively charged components of the bacterial membrane. MFQ + polymyxin B caused significantly greater curvature in the simulated membrane, indicating greater damage than standalone drug treatment. Finally,\n                      <jats:italic>in vivo<\/jats:italic>\n                      assays showed that MFQ + polymyxin B rescued\n                      <jats:italic>Galleria mellonella<\/jats:italic>\n                      larvae infected with\n                      <jats:italic>A. baumannii<\/jats:italic>\n                      . In conclusion, membrane-active agents such as MFQ may warrant further investigation as a potential components of gram-negative infection treatment, particularly in combination with polymyxin B.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>\n                      Antimicrobial resistance is a threat globally, and new treatments are urgently needed to combat the rise of multidrug-resistant bacteria. However, the development of anti-infectives has declined over the last two decades due to regulatory, financial and long-term requirement related challenges. In this study, we examined the membrane interactions of the antiparasitic agent mefloquine (MFQ) in combination with polymyxin B, using both\n                      <jats:italic>in vitro<\/jats:italic>\n                      and\n                      <jats:italic>in silico<\/jats:italic>\n                      approaches to evaluate their potential efficacy against gram-negative bacterial infections. We investigated the interaction of MFQ with lipid bilayers to understand the mechanism through which antibacterial activity is exerted. The piperidine moiety of MFQ plays a critical role in its interaction with the lipid bilayer and facilitates membrane permeabilization. In contrast, the membrane permeabilizer polymyxin B is associated with significant neurotoxicity and nephrotoxicity. Our findings highlight the potential of membrane-acting compounds, such as MFQ, to enhance combinatorial activity while mitigating polymyxin B-associated toxicity.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.04016-24","type":"journal-article","created":{"date-parts":[[2025,2,25]],"date-time":"2025-02-25T09:08:27Z","timestamp":1740474507000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":10,"title":["Mefloquine reduces the bacterial membrane fluidity of\n                    <i>Acinetobacter baumannii<\/i>\n                    and distorts the bacterial membrane when combined with polymyxin B"],"prefix":"10.1128","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6107-3754","authenticated-orcid":true,"given":"Nagendran","family":"Tharmalingam","sequence":"first","affiliation":[{"name":"Houston Methodist Hospital and Houston Methodist Research Institute","place":["Houston, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harikrishna Sekar","family":"Jayanthan","sequence":"additional","affiliation":[{"name":"Vanderblit University","place":["Nashville, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenna","family":"Port","sequence":"additional","affiliation":[{"name":"Tufts University","place":["Boston, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernanda Cristina Possamai","family":"Rossatto","sequence":"additional","affiliation":[{"name":"Houston Methodist Hospital and Houston Methodist Research Institute","place":["Houston, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4624-0777","authenticated-orcid":true,"given":"Eleftherios","family":"Mylonakis","sequence":"additional","affiliation":[{"name":"Houston Methodist Hospital and Houston Methodist Research Institute","place":["Houston, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tim.2021.11.008"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2017.00055"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro.2017.148"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1086\/533452"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00058-16"},{"key":"e_1_3_4_7_2","unstructured":"World Health Organization. 2024. 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