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Derived from secondary endosymbiosis, the apicoplast depends on novel, but largely cryptic, mechanisms for protein\/lipid import and organelle inheritance during parasite replication. These critical biogenesis pathways present untapped opportunities to discover new parasite-specific drug targets. We used an innovative screen to identify actinonin as having a novel mechanism-of-action inhibiting apicoplast biogenesis. Resistant mutation, chemical-genetic interaction, and biochemical inhibition demonstrate that the unexpected target of actinonin in P. falciparum and Toxoplasma gondii is FtsH1, a homolog of a bacterial membrane AAA+ metalloprotease. PfFtsH1 is the first novel factor required for apicoplast biogenesis identified in a phenotypic screen. Our findings demonstrate that FtsH1 is a novel and, importantly, druggable antimalarial target. Development of FtsH1 inhibitors will have significant advantages with improved drug kinetics and multistage efficacy against multiple human parasites.<\/jats:p>","DOI":"10.7554\/elife.29865","type":"journal-article","created":{"date-parts":[[2017,8,18]],"date-time":"2017-08-18T08:00:21Z","timestamp":1503043221000},"source":"Crossref","is-referenced-by-count":68,"title":["Small molecule inhibition of apicomplexan FtsH1 disrupts plastid biogenesis in human pathogens"],"prefix":"10.7554","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2707-2912","authenticated-orcid":true,"given":"Katherine","family":"Amberg-Johnson","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Stanford Medical School, Stanford, United States"},{"name":"Microbiology and Immunology, Stanford Medical School, Stanford, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjay B","family":"Hari","sequence":"additional","affiliation":[{"name":"Department of Biology, Massachusetts Institute of Technology, Cambridge, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suresh M","family":"Ganesan","sequence":"additional","affiliation":[{"name":"Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hernan A","family":"Lorenzi","sequence":"additional","affiliation":[{"name":"Department of Infectious Disease, The J. Craig Venter Institute, Maryland, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert T","family":"Sauer","sequence":"additional","affiliation":[{"name":"Department of Biology, Massachusetts Institute of Technology, Cambridge, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacquin C","family":"Niles","sequence":"additional","affiliation":[{"name":"Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3974-3816","authenticated-orcid":true,"given":"Ellen","family":"Yeh","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Stanford Medical School, Stanford, United States"},{"name":"Microbiology and Immunology, Stanford Medical School, Stanford, United States"},{"name":"Department of Pathology, Stanford Medical School, Stanford, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2017,8,18]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"4525","DOI":"10.1073\/pnas.0307122101","article-title":"Yeast genome-wide drug-induced haploinsufficiency screen to determine drug mode of action","volume":"101","author":"Baetz","year":"2004","journal-title":"PNAS"},{"key":"bib2","doi-asserted-by":"publisher","first-page":"3066","DOI":"10.1073\/pnas.0600031103","article-title":"The molecular architecture of the metalloprotease FtsH","volume":"103","author":"Bieniossek","year":"2006","journal-title":"PNAS"},{"key":"bib3","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1515\/hsz-2016-0302","article-title":"When, how and why? 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