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Leucinostatins from the fungus <jats:italic>Purpureocillium lilacinum<\/jats:italic> inhibited the transmission of <jats:italic>Plasmodium falciparum<\/jats:italic> to mosquitoes via contact.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Here, we modified the\u00a0leucinostatin B (LB) C-terminus to make derivatives and examined their inhibition against malaria transmission to mosquitoes. Fluorescence-labeled leucinostatins were incubated with intact gametocytes and were examined under microscopy to detect the targets of leucinostatins. We also analyzed leucinostatins\u2019 general cytotoxicity and hemolysis.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>The results showed that the derivatives with \u2013H, \u2013CH<jats:sub>3<\/jats:sub>, \u2013Atto495, and \u2013Biotin at C-terminus had EC<jats:sub>50<\/jats:sub> of 1.5\u00a0nM, 0.2\u00a0nM, 4.2\u00a0nM, and 42\u00a0nM, respectively. Atto495 and biotin are similar in size and much bigger than -CH<jats:sub>3<\/jats:sub> and -H. Based on reverse-phase HPLC elution time, we found that LB-Biotin had much higher hydrophobicity than the others, consistent with its lowest malaria transmission-blocking activity. Fluorescence microscopy showed that LB-Atto495 colocalized with mitochondria inside intact <jats:italic>P<\/jats:italic>. <jats:italic>falciparum<\/jats:italic> gametocytes. We found that leucinostatin A significantly inhibited the proliferation of\u00a0human nucleated\u00a0cells with IC<jats:sub>50<\/jats:sub> around 47\u00a0nM and it did not lyse erythrocytes at 100\u00a0\u03bcM.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>We conclude that the leucinostatins pass through the cytoplasmic membrane without lysing cells and interact with molecules specifically in mitochondria. Therefore, leucinostatins should be ideal inhibitors against mobile parasites, such as ookinetes and sporozoites, during malaria transmission.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Graphical Abstract<\/jats:title>\n                \n              <\/jats:sec>","DOI":"10.1186\/s13071-024-06608-8","type":"journal-article","created":{"date-parts":[[2024,12,20]],"date-time":"2024-12-20T05:53:04Z","timestamp":1734673984000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Leucinostatins target Plasmodium mitochondria to block malaria transmission"],"prefix":"10.1186","volume":"17","author":[{"given":"Guodong","family":"Niu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,12,20]]},"reference":[{"key":"6608_CR1","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1016\/S1473-3099(18)30068-9","volume":"18","author":"R Amato","year":"2018","unstructured":"Amato R, Pearson RD, Almagro-Garcia J, Amaratunga C, Lim P, Suon S, et al. Origins of the current outbreak of multidrug-resistant malaria in southeast Asia: a retrospective genetic study. Lancet Infect Dis. 2018;18:337\u201345. https:\/\/doi.org\/10.1016\/S1473-3099(18)30068-9.","journal-title":"Lancet Infect Dis"},{"key":"6608_CR2","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1186\/s12936-019-2656-7","volume":"18","author":"FT Tokponnon","year":"2019","unstructured":"Tokponnon FT, Sissinto Y, Ogouyemi AH, Adeothy AA, Adechoubou A, Houansou T, et al. Implications of insecticide resistance for malaria vector control with long-lasting insecticidal nets: evidence from health facility data from Benin. Malar J. 2019;18:37. https:\/\/doi.org\/10.1186\/s12936-019-2656-7.","journal-title":"Malar J"},{"key":"6608_CR3","doi-asserted-by":"publisher","DOI":"10.3390\/vaccines10050713","author":"AY Nadeem","year":"2022","unstructured":"Nadeem AY, Shehzad A, Islam SU, Al-Suhaimi EA, Lee YS. 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