{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:49:28Z","timestamp":1768510168271,"version":"3.49.0"},"posted":{"date-parts":[[2024,1,11]]},"group-title":"Microbiology","reference-count":65,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,1,11]]},"abstract":"<jats:title>Summary<\/jats:title>\n                <jats:p>\n                  Malaria, caused by\n                  <jats:italic>Plasmodium falciparum,<\/jats:italic>\n                  remains a significant health burden. A barrier for developing anti-malarial drugs is the ability of the parasite to rapidly generate resistance. We demonstrated that Salinipostin A (SalA), a natural product, kills parasites by inhibiting multiple lipid metabolizing serine hydrolases, a mechanism with a low propensity for resistance. Given the difficulty of employing natural products as therapeutic agents, we synthesized a library of lipidic mixed alkyl\/aryl phosphonates as bioisosteres of SalA. Two constitutional isomers exhibited divergent anti-parasitic potencies which enabled identification of therapeutically relevant targets. We also confirm that this compound kills parasites through a mechanism that is distinct from both SalA and the pan-lipase inhibitor, Orlistat. Like SalA, our compound induces only weak resistance, attributable to mutations in a single protein involved in multidrug resistance. These data suggest that mixed alkyl\/aryl phosphonates are a promising, synthetically tractable anti-malarials with a low-propensity to induce resistance.\n                <\/jats:p>","DOI":"10.1101\/2024.01.11.575224","type":"posted-content","created":{"date-parts":[[2024,1,11]],"date-time":"2024-01-11T22:10:16Z","timestamp":1705011016000},"source":"Crossref","is-referenced-by-count":0,"title":["Mixed Alkyl\/Aryl Phosphonates Identify Metabolic Serine Hydrolases as Antimalarial Targets"],"prefix":"10.64898","author":[{"given":"John M.","family":"Bennett","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sunil K.","family":"Narwal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie","family":"Kabeche","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Abegg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fiona","family":"Hackett","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomas","family":"Yeo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Veronica L.","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryan K.","family":"Muir","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Franco F.","family":"Faucher","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Scott","family":"Lovell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7442-3810","authenticated-orcid":false,"given":"Michael J.","family":"Blackman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander","family":"Adibekian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ellen","family":"Yeh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David A.","family":"Fidock","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3753-4412","authenticated-orcid":false,"given":"Matthew","family":"Bogyo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024011304100649000_2024.01.11.575224v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.579"},{"key":"2024011304100649000_2024.01.11.575224v1.2","doi-asserted-by":"publisher","DOI":"10.1186\/s12915-021-01042-z"},{"key":"2024011304100649000_2024.01.11.575224v1.3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1314981"},{"key":"2024011304100649000_2024.01.11.575224v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2021.08.013"},{"key":"2024011304100649000_2024.01.11.575224v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3620"},{"key":"2024011304100649000_2024.01.11.575224v1.6","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.2c10819"},{"key":"2024011304100649000_2024.01.11.575224v1.7","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2101746"},{"key":"2024011304100649000_2024.01.11.575224v1.8","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-06221-1"},{"key":"2024011304100649000_2024.01.11.575224v1.9","doi-asserted-by":"publisher","DOI":"10.15252\/msb.202110798"},{"key":"2024011304100649000_2024.01.11.575224v1.10","unstructured":"By-Nc-Sa, C ., 2022. 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