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The potential for the development of drug resistance against plasmepsin X (PMX)-selective inhibitors and dual plasmepsin IX\/X (PMIX\/X) inhibitors was investigated in\n                    <jats:italic>Plasmodium falciparum<\/jats:italic>\n                    . A series of PMX-selective (WM4, WM76, WM92) and PMIX\/X dual inhibitors (WM382, WM09, WM42) were characterised for potency against parasite growth and enzyme inhibition.\n                    <jats:italic>In vitro<\/jats:italic>\n                    selection experiments showed that all compounds had a high barrier to resistance, although parasites with reduced sensitivity to PMX\u2011selective inhibitors could still be selected. Resistance mechanisms involved\n                    <jats:italic>pmx<\/jats:italic>\n                    gene amplification and point mutations (D245N, S315P, S359P, I363L) that alter inhibitor binding. Recombinant expression and Michaelis\u2013Menten kinetics demonstrated that these mutations impair drug binding whilst preserving PMX catalytic function. Reverse genetics confirmed that introducing these mutations into the\n                    <jats:italic>pmx<\/jats:italic>\n                    gene resulted in decreased potency of the inhibitors. In this study, resistance to the PMIX\/X dual inhibitors evaluated here could not be selected, despite prolonged selection pressure. Antimalarial Resistome Barcoding (AReBar) assays confirmed the absence of pre-existing resistance to either inhibitor class. Critically, PMIX\/X dual inhibitors maintained efficacy against parasites with decreased sensitivity to PMX-selective compounds. These findings demonstrate that dual PMIX\/X inhibitors present a substantially higher barrier to resistance than PMX-selective inhibitors, informing antimalarial drug development strategies and highlighting dual-target inhibition as a promising approach to mitigate resistance risks.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1014068","type":"journal-article","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T17:54:31Z","timestamp":1788890071000},"page":"e1014068","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dual plasmepsin IX and X inhibitors are refractory to development of resistance"],"prefix":"10.1371","volume":"22","author":[{"given":"Paola","family":"Favuzza","sequence":"first","affiliation":[{"name":"The Walter and Eliza Hall Institute of Medical Research","place":["Parkville, Victoria, Australia"]},{"name":"The University of Melbourne","place":["Melbourne, Victoria, Australia"],"department":["Department of Medical Biology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madeline G.","family":"Dans","sequence":"additional","affiliation":[{"name":"The Walter and Eliza Hall Institute of Medical Research","place":["Parkville, Victoria, Australia"]},{"name":"The University of Melbourne","place":["Melbourne, Victoria, Australia"],"department":["Department of Medical Biology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyin","family":"Su","sequence":"additional","affiliation":[{"name":"The Walter and Eliza Hall Institute of Medical Research","place":["Parkville, Victoria, Australia"]},{"name":"The University of Melbourne","place":["Melbourne, Victoria, Australia"],"department":["Department of Medical Biology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer K.","family":"Thompson","sequence":"additional","affiliation":[{"name":"The Walter and Eliza Hall Institute of Medical Research","place":["Parkville, Victoria, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony N.","family":"Hodder","sequence":"additional","affiliation":[{"name":"The Walter and Eliza Hall Institute of Medical Research","place":["Parkville, Victoria, Australia"]},{"name":"The University of Melbourne","place":["Melbourne, Victoria, Australia"],"department":["Department of Medical Biology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Ngo","sequence":"additional","affiliation":[{"name":"The Walter and Eliza Hall Institute of Medical Research","place":["Parkville, Victoria, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1561-0074","authenticated-orcid":true,"given":"Jocelyn Sietsma","family":"Penington","sequence":"additional","affiliation":[{"name":"The Walter and Eliza Hall Institute of Medical Research","place":["Parkville, Victoria, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danushka S.","family":"Marapana","sequence":"additional","affiliation":[{"name":"The Walter and Eliza Hall Institute of Medical Research","place":["Parkville, Victoria, Australia"]},{"name":"The University of Melbourne","place":["Melbourne, Victoria, Australia"],"department":["Department of Medical Biology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerzy M.","family":"Dziekan","sequence":"additional","affiliation":[{"name":"The Walter and Eliza Hall Institute of Medical Research","place":["Parkville, Victoria, Australia"]},{"name":"The University of Melbourne","place":["Melbourne, Victoria, Australia"],"department":["Department of Medical Biology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony T.","family":"Papenfuss","sequence":"additional","affiliation":[{"name":"The Walter and Eliza Hall Institute of Medical Research","place":["Parkville, Victoria, Australia"]},{"name":"The University of Melbourne","place":["Melbourne, Victoria, Australia"],"department":["Department of Medical Biology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"de Lera Ruiz","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc.","place":["West Point, Pennsylvania, United States of America"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachael","family":"Coyle","sequence":"additional","affiliation":[{"name":"Wellcome Sanger Institute, Wellcome Genome Campus","place":["Hinxton, United Kingdom"]},{"name":"Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee","place":["Dundee, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus C. S.","family":"Lee","sequence":"additional","affiliation":[{"name":"Wellcome Sanger Institute, Wellcome Genome Campus","place":["Hinxton, United Kingdom"]},{"name":"Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee","place":["Dundee, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John A.","family":"McCauley","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc.","place":["West Point, Pennsylvania, United States of America"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kym","family":"Lowes","sequence":"additional","affiliation":[{"name":"The Walter and Eliza Hall Institute of Medical Research","place":["Parkville, Victoria, Australia"]},{"name":"The University of Melbourne","place":["Melbourne, Victoria, Australia"],"department":["Department of Medical Biology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David B.","family":"Olsen","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc.","place":["West Point, Pennsylvania, United States of America"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brad E.","family":"Sleebs","sequence":"additional","affiliation":[{"name":"The Walter and Eliza Hall Institute of Medical Research","place":["Parkville, Victoria, Australia"]},{"name":"The University of Melbourne","place":["Melbourne, Victoria, Australia"],"department":["Department of Medical Biology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5145-9004","authenticated-orcid":true,"given":"Alan F.","family":"Cowman","sequence":"additional","affiliation":[{"name":"The Walter and Eliza Hall Institute of Medical Research","place":["Parkville, Victoria, Australia"]},{"name":"The University of Melbourne","place":["Melbourne, Victoria, Australia"],"department":["Department of Medical Biology"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,9,8]]},"reference":[{"key":"ppat.1014068.ref001","unstructured":"WHO. 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