{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T14:55:46Z","timestamp":1785596146014,"version":"3.56.0"},"reference-count":101,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2022,6,14]],"date-time":"2022-06-14T00:00:00Z","timestamp":1655164800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"die BIOPEPTM Peptide Fund"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibiotics"],"abstract":"<jats:p>Previous research found that the six major cyclodecapeptides from the tyrothricin complex, produced by Brevibacillus parabrevis, showed potent activity against chloroquine sensitive (CQS) Plasmodium falciparum. The identity of the aromatic residues in the aromatic dipeptide unit in cyclo-(D-Phe1-Pro2-(Phe3\/Trp3)-D-Phe4\/D-Trp4)-Asn5-Gln6-(Tyr7\/Phe7\/Trp7)-Val8-(Orn9\/Lys9)-Leu10 was proposed to have an important role in activity. CQS and resistant (CQR) P. falciparum strains were challenged with three representative cyclodecapeptides. Our results confirmed that cyclodecapeptides from tyrothricin had significantly higher antiplasmodial activity than the analogous gramicidin S, rivaling that of CQ. However, the previously hypothesized size and hydrophobicity dependent activity for these peptides did not hold true for P. falciparum strains, other than for the CQS 3D7 strain. The Tyr7 in tyrocidine A (TrcA) with Phe3-D-Phe4 seem to be related with loss in activity correlating with CQ antagonism and resistance, indicating a shared target and\/or resistance mechanism in which the phenolic groups play a role. Phe7 in phenycidine A, the second peptide containing Phe3-D-Phe4, also showed CQ antagonism. Conversely, Trp7 in tryptocidine C (TpcC) with Trp3-D-Trp4 showed improved peptide selectivity and activity towards the more resistant strains, without overt antagonism towards CQ. However, TpcC lead to similar parasite stage inhibition and parasite morphology changes than previously observed for TrcA. The disorganization of chromatin packing and neutral lipid structures, combined with amorphous hemozoin crystals, could account for halted growth in late trophozoite\/early schizont stage and the nanomolar non-lytic activity of these peptides. These targets related to CQ antagonism, changes in neural lipid distribution, leading to hemozoin malformation, indicate that the tyrothricin cyclodecapeptides and CQ share a target in the malaria parasite. The differing activities of these cyclic peptides towards CQS and CQR P. falciparum strains could be due to variable target interaction in multiple modes of activity. This indicated that the cyclodecapeptide activity and parasite resistance response depended on the aromatic residues in positions 3, 4 and 7. This new insight on these natural cyclic decapeptides could also benefit the design of unique small peptidomimetics in which activity and resistance can be modulated.<\/jats:p>","DOI":"10.3390\/antibiotics11060801","type":"journal-article","created":{"date-parts":[[2022,6,14]],"date-time":"2022-06-14T23:50:14Z","timestamp":1655250614000},"page":"801","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Antiplasmodial Cyclodecapeptides from Tyrothricin Share a Target with Chloroquine"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3581-7179","authenticated-orcid":false,"given":"Adrienne N.-N.","family":"Leussa","sequence":"first","affiliation":[{"name":"BioPep Peptide Group, Department of Biochemistry, University of Stellenbosch, Stellenbosch 7600, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7198-9213","authenticated-orcid":false,"given":"Marina","family":"Rautenbach","sequence":"additional","affiliation":[{"name":"BioPep Peptide Group, Department of Biochemistry, University of Stellenbosch, Stellenbosch 7600, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,14]]},"reference":[{"key":"ref_1","unstructured":"(2022, February 28). World Health Organization Global Collaborator Group, World Malaria Report 2021: An In-Depth Update on Global and Regional Malaria Data and Trends. World Health Organization Press. Available online: www.mmv.org\/newsroom\/publications\/world-malaria-report-2012."},{"key":"ref_2","unstructured":"Galal, S. (2022, February 28). Coronavirus Deaths in Africa as of November 22, 2021, by Country. Available online: www.statista.com\/statistics\/1170530\/coronavirus-deaths-in-africa."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/0169-4758(87)90147-5","article-title":"Spread of chloroquine resistance in Plasmodium Falciparum","volume":"3","author":"Payne","year":"1987","journal-title":"Parasitol. Today"},{"key":"ref_4","first-page":"271","article-title":"Current understanding of the molecular basis of chloroquine-resistance in Plasmodium falciparum","volume":"52","author":"Jiang","year":"2006","journal-title":"J. Postgr. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1056\/NEJMe0905159","article-title":"Malaria control-addressing challenges to ambitious goals","volume":"361","author":"Campbell","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1186\/1475-2875-12-118","article-title":"Artemisinin resistance in rodent malaria-mutation in the AP2 adaptor mu-chain suggests involvement of endocytosis and membrane protein trafficking","volume":"12","author":"Henriques","year":"2013","journal-title":"Malar. J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1960","DOI":"10.1016\/S0140-6736(05)67787-2","article-title":"Resistance of Plasmodium falciparum field isolates to in-vitro artemether and point mutations of the SERCA-type PfATPase6","volume":"366","author":"Jambou","year":"2005","journal-title":"Lancet"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/j.meegid.2012.12.014","article-title":"Mutation analysis in pfmdr1 and pfmrp1 as potential candidate genes for artemisinin resistance in Plasmodium falciparum clinical isolates 4 years after implementation of artemisinin combination therapy in Iran","volume":"14","author":"Pirahmadi","year":"2013","journal-title":"Infect. Genet. Evol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.ijantimicag.2012.12.007","article-title":"Antimalarial drug resistance: A review of the biology and strategies to delay emergence and spread","volume":"41","author":"Klein","year":"2013","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/S0169-4758(97)85284-2","article-title":"Altered membrane phospholipid asymmetry in Plasmodium falciparum-infected erythrocytes","volume":"13","author":"Sherman","year":"1997","journal-title":"Parasitol. Today"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/0169-4758(90)90174-3","article-title":"Antigens on the Plasmodium falciparum infected erythrocyte surface are not parasite derived","volume":"6","author":"Sherman","year":"1990","journal-title":"Parasitol. Today"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/0166-6851(90)90210-D","article-title":"Phospholipid composition, cholesterol content and cholesterol exchange in Plasmodium falciparum-infected red cells","volume":"38","author":"Maguire","year":"1990","journal-title":"Mol. Biochem. Parasitol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1016\/0035-9203(84)90227-X","article-title":"Altered red cell membrane fluidity during schizogonic development malarial parasites Plasmodium falciparum and P. lophurae","volume":"78","author":"Sherman","year":"1984","journal-title":"Trans. R. Soc. Trop. Med. Hyg."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1242\/jcs.106.1.237","article-title":"The origin of parasitophorous vacuole membrane lipids in malaria-infected erythrocytes","volume":"106","author":"Ward","year":"1993","journal-title":"J. Cell Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1017\/S0031182000000792","article-title":"Changes in the membrane microviscosity of mouse red blood cells infected with Plasmodium berghei detected using n-9-anthroyloxy fatty acid fluorescent probes","volume":"80","author":"Howard","year":"2009","journal-title":"Parasitology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/0166-6851(83)90114-7","article-title":"Increased fluidity of Plasmodium berghei-infected mouse red blood cell membranes detected by electron spin resonance spectroscopy","volume":"7","author":"Allred","year":"1983","journal-title":"Mol. Biochem. Parasitol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1126\/science.3006251","article-title":"Perturbation of red cell membrane structure during intracellular maturation of Plasmodium falciparum","volume":"232","author":"Taraschi","year":"1986","journal-title":"Science"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/0005-2736(86)90418-9","article-title":"Selectivity properties of pores induced in host erythrocyte membrane by Plasmodium falciparum. Effect of parasite maturation","volume":"861","author":"Ginsburg","year":"1986","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/0005-2736(82)90178-X","article-title":"Alterations in membrane permeability of malaria-infected human erythrocytes are related to the growth stage of the parasite","volume":"687","author":"Kutner","year":"1982","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/0166-6851(85)90059-3","article-title":"Characterization of permeation pathways appearing in the host membrane of Plasmodium falciparum infected red blood cells","volume":"14","author":"Ginsburg","year":"1985","journal-title":"Mol. Biochem. Parasitol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1002\/jcp.1041140215","article-title":"Permselectivity changes in malaria Plasmodium falciparum infected human red blood cell membranes","volume":"114","author":"Kutner","year":"1983","journal-title":"J. Cell. Physiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/0166-6851(83)90008-7","article-title":"New permeability pathways induced in membranes of Plasmodium falciparum infected erythrocytes","volume":"8","author":"Ginsburg","year":"1983","journal-title":"Mol. Biochem. Parasitol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1186\/1475-2875-11-256","article-title":"Anti-plasmodial action of de novo designed, cationic, lysine-branched, amphipathic, helical peptides","volume":"11","author":"Kaushik","year":"2012","journal-title":"Malar. J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1713","DOI":"10.1128\/AAC.01342-07","article-title":"The antimicrobial peptide NK-2, the core region of mammalian NK-lysin, kills intraerythrocytic Plasmodium falciparum","volume":"52","author":"Gelhaus","year":"2008","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1042\/bj2740121","article-title":"Modification of host cell membrane lipid composition by the intra-erythrocytic human malaria parasite","volume":"274","author":"Hsiao","year":"1991","journal-title":"Biochem. J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1016\/j.bcp.2005.12.012","article-title":"Selective lysis of erythrocytes infected with the trophozoite stage of Plasmodium falciparum by polyene macrolide antibiotics","volume":"71","author":"Wiehart","year":"2006","journal-title":"Biochem. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1582","DOI":"10.1016\/j.bbamem.2008.10.020","article-title":"Antimicrobial peptide mimics for improved therapeutic properties","volume":"1788","author":"Rotem","year":"2009","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1093\/infdis\/75.3.179","article-title":"The antimalarial activity of tyrothricin against Plasmodium gallinaceum","volume":"75","author":"Taliaferro","year":"1944","journal-title":"J. Infect. Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1007\/BF00932413","article-title":"Stage-dependent effects of analogs of gramicidin A on the growth of Plasmodium falciparum in vitro","volume":"81","author":"Roelofsen","year":"1995","journal-title":"Parasitol. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1007\/s004360050230","article-title":"Coppens-Burkunk, G.W.M.; Kronenburg, N.A.; Braga Fernandes Vis, M.A. Roelofsen, B.; Op den Kamp, J.A.F. Tryptophan-N-formylated gramicidin causes growth inhibition of Plasmodium falciparum by induction of potassium efflux from infected erythrocytes","volume":"83","year":"1997","journal-title":"Parasitol. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.cbpa.2017.02.006","article-title":"Cyclic peptide therapeutics: Past, present and future","volume":"38","author":"Zorzi","year":"2017","journal-title":"Curr. Opin. Chem. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1891","DOI":"10.1021\/np800409z","article-title":"Isolation of aerucyclamides C and D and structure revision of microcyclamide 7806A: Heterocyclic ribosomal peptides from Microcystis aeruginosa PCC 7806 and their antiparasite evaluation","volume":"71","author":"Portmann","year":"2008","journal-title":"J. Nat. Prod."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1021\/acs.jnatprod.6b00758","article-title":"Octaminomycins A and B, cyclic octadepsipeptides active against Plasmodium falciparum","volume":"80","author":"Jang","year":"2017","journal-title":"J. Nat. Prod."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2433","DOI":"10.1002\/cbic.201500472","article-title":"Gift from nature: Cyclomarin A kills mycobacteria and malaria parasites by distinct modes of action","volume":"16","author":"Buerstner","year":"2015","journal-title":"ChemBioChem"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/0168-1176(92)87015-7","article-title":"Characterisation of the tyrocidine and gramicidin fractions of the tyrothricin complex from Bacillus brevis using liquid chromatography and mass spectrometry","volume":"122","author":"Tang","year":"1992","journal-title":"Int. J. Mass Spectrom. Ion Processes"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1488","DOI":"10.1016\/j.bbamem.2007.01.015","article-title":"Inhibition of malaria parasite blood stages by tyrocidines, membrane-active cyclic peptide antibiotics from Bacillus Brevis","volume":"1768","author":"Rautenbach","year":"2007","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"6620","DOI":"10.1128\/AEM.00881-07","article-title":"The ability of Aneurinibacillus migulanus (Bacillus brevis) to produce the antibiotic gramicidin S is correlated with phenotype variation","volume":"7320","author":"Berditsch","year":"2007","journal-title":"Appl. Environ. Microbiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"5053","DOI":"10.1021\/acs.biomac.0c01202","article-title":"2020. Poly-N-vinylpyrrolidone antimalaria conjugates of membrane-disruptive peptides","volume":"21","author":"Jokonya","year":"2020","journal-title":"Biomacromolecules"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/S0166-6851(99)00008-0","article-title":"The fate of ferriprotorphyrin IX in malaria infected erythrocytes in conjunction with the mode of action of antimalarial drugs","volume":"99","author":"Zhang","year":"1999","journal-title":"Mol. Biochem. Parasitol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"223","DOI":"10.4269\/ajtmh.1985.34.223","article-title":"Toxic heme in sickle cells: An explanation for death of malaria parasites","volume":"342","author":"Orjih","year":"1985","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2868","DOI":"10.3390\/molecules14082868","article-title":"De, Egan, T.J.; de Villiers, K.A.; Egan, T.J. Recent advances in the discovery of haem-targeting drugs for malaria and schistosomiasis","volume":"14","author":"Villiers","year":"2009","journal-title":"Molecules"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1038\/214937a0","article-title":"Morphological effects of chloroquine on Plasmodium berghei in mice","volume":"214","author":"Macomber","year":"1967","journal-title":"Nature"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1038\/214935a0","article-title":"Mode of action of chloroquine on Plasmodium berghei and P. cynomolgi","volume":"214","author":"Warhurst","year":"1967","journal-title":"Nature"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1042\/BJ20060986","article-title":"The role of neutral lipid nanospheres in Plasmodium falciparum haem crystallization","volume":"402","author":"Pisciotta","year":"2007","journal-title":"Biochem. J."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.molbiopara.2007.11.005","article-title":"Haemozoin formation","volume":"157","author":"Egan","year":"2008","journal-title":"Mol. Biochem. Parasitol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1186\/1475-2875-11-337","article-title":"Neutral lipids associated with haemozoin mediate efficient and rapid \u03b2-haematin formation at physiological pH, temperature and ionic composition","volume":"11","author":"Ambele","year":"2012","journal-title":"Malar. J."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"11188","DOI":"10.1073\/pnas.1118120109","article-title":"Oriented nucleation of hemozoin at the digestive vacuole membrane in Plasmodium Falciparum","volume":"109","author":"Kapishnikov","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Huy, N.T., Shima, Y., Maeda, A., Men, T.T., Hirayama, K., Hirase, A., Miyazawa, A., and Kamei, K. (2013). Phospholipid membrane-mediated hemozoin formation: The effects of physical properties and evidence of membrane surrounding hemozoin. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0070025"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/s10863-011-9335-x","article-title":"On the mechanisms involved in biological heme crystallization","volume":"43","author":"Stiebler","year":"2011","journal-title":"J. Bioenerg. Biomembr."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"10107","DOI":"10.1021\/bi101397u","article-title":"The neutral lipid composition present in the digestive vacuole of Plasmodium falciparum concentrates heme and mediates \u03b2-hematin formation with an unusually low activation energy","volume":"49","author":"Hoang","year":"2010","journal-title":"Biochemistry"},{"key":"ref_51","first-page":"237","article-title":"Lipids and the malarial parasite","volume":"55","author":"Holz","year":"1977","journal-title":"Bull. World Health Org."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1042\/bj2830619","article-title":"Saturable and non-saturable components of choline transport in Plasmodium-infected mammalian erythrocytes: Possible role of experimental conditions","volume":"283","author":"Ancelin","year":"1992","journal-title":"Biochem. J."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.molbiopara.2003.08.017","article-title":"Neutral lipid synthesis and storage in the intraerythrocytic stages of Plasmodium Falciparum","volume":"135","author":"Vielemeyer","year":"2004","journal-title":"Mol. Biochem. Parasitol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.1128\/EC.2.5.1128-1131.2003","article-title":"Neutral lipid analysis reveals elevation of acylglycerols and lack of cholesterol esters in Plasmodium falciparum-infected erythrocytes","volume":"2","author":"Nawabi","year":"2003","journal-title":"Eukaryot. Cell"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"15475","DOI":"10.1021\/bi00047a012","article-title":"Anchoring of tryptophan and tyrosine analogues at the hydrocarbon polar boundary in model membrane vesicles: Parallax analysis of fluorescence quenching induced by nitroxide-labeled phospholipids","volume":"34","author":"Kachel","year":"1995","journal-title":"Biochemistry"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1007\/BF02704101","article-title":"Membrane interfacial localization of aromatic amino acids and membrane protein function","volume":"31","author":"Kelkar","year":"2006","journal-title":"J. Biosci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2046","DOI":"10.1529\/biophysj.105.080275","article-title":"Indole localization in lipid membranes revealed by molecular simulation","volume":"91","author":"Norman","year":"2006","journal-title":"Biophys. J."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1016\/S0006-3495(99)77284-X","article-title":"Molecular dynamics study of substance P peptides in a biphasic membrane mimic","volume":"76","author":"Wymore","year":"1999","journal-title":"Biophys. J."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"6667","DOI":"10.1016\/j.bmc.2007.08.007","article-title":"Development of tyrocidine A analogues with improved antibacterial activity","volume":"15","author":"Marques","year":"2007","journal-title":"Bioorg. Med. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/S0005-2736(99)00201-1","article-title":"Structural features of helical antimicrobial peptides: Their potential to modulate activity on model membranes and biological cells","volume":"1462","author":"Dathe","year":"1999","journal-title":"Biochim. Biophys. Acta Biomem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"5589","DOI":"10.1046\/j.1432-1033.2001.02494.x","article-title":"Amphipathic \u03b1 helical antimicrobial peptides: A systematic study of the effects of structural and physical properties on biological activity","volume":"268","author":"Giangaspero","year":"2001","journal-title":"Eur. J. Biochem."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"3185","DOI":"10.1073\/pnas.71.8.3185","article-title":"Specific recognition of single-stranded regions in ultraviolet-irradiated and heat-denatured DNA by tryptophan-containing peptides","volume":"71","author":"Toulme","year":"1974","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"e00802-18","DOI":"10.1128\/mBio.00802-18","article-title":"The multifaceted antibacterial mechanisms of the pioneering peptide antibiotics tyrocidine and gramicidin S","volume":"9","author":"Wenzel","year":"2018","journal-title":"mBio"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1938","DOI":"10.1093\/molbev\/msh205","article-title":"The malaria parasite\u2019s chloroquine resistance transporter is a member of the drug\/metabolite transporter superfamily","volume":"21","author":"Martin","year":"2004","journal-title":"Mol. Biol. Evol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1016\/j.ijpara.2010.04.001","article-title":"Transporters as mediators of drug resistance in Plasmodium Falciparum","volume":"40","author":"Sanchez","year":"2010","journal-title":"Int. J. Parasitol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1111\/j.1365-2958.2006.05511.x","article-title":"Mutations in transmembrane domains 1, 4 and 9 of the Plasmodium falciparum chloroquine resistance transporter alter susceptibility to chloroquine, quinine and quinidine","volume":"63","author":"Cooper","year":"2007","journal-title":"Mol. Microbiol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"18883","DOI":"10.1073\/pnas.0911317106","article-title":"Geographic patterns of Plasmodium falciparum drug resistance distinguished by differential responses to amodiaquine and chloroquine","volume":"106","author":"Twu","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1016\/j.molcel.2004.09.012","article-title":"Evidence for a central role for PfCRT in conferring Plasmodium falciparum resistance to diverse antimalarial agents","volume":"15","author":"Johnson","year":"2004","journal-title":"Mol. Cell"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1680","DOI":"10.1126\/science.1175667","article-title":"Chloroquine transport via the malaria parasite\u2019s chloroquine resistance transporter","volume":"325","author":"Martin","year":"2009","journal-title":"Science"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"3922","DOI":"10.1038\/s41467-020-17781-6","article-title":"The natural function of the malaria parasite\u2019s chloroquine resistance transporter","volume":"11","author":"Shafik","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1016\/S1097-2765(05)00077-8","article-title":"Mutations in the P. falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance","volume":"6","author":"Fidock","year":"2000","journal-title":"Mol. Cell"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1083\/jcb.113.5.1033","article-title":"A P-glycoprotein homologue of Plasmodium falciparum is localized on the digestive vacuole","volume":"113","author":"Cowman","year":"1991","journal-title":"J. Cell Biol."},{"key":"ref_73","first-page":"813","article-title":"Chromosome size variation occurs in cloned Plasmodium falciparum on in vitro cultivation","volume":"11","author":"Wellems","year":"1988","journal-title":"Rev. Bras. Genet."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1038\/nchembio.215","article-title":"Genetic mapping of targets mediating differential chemical phenotypes in Plasmodium falciparum","volume":"5","author":"Yuan","year":"2009","journal-title":"Nat. Chem. Biol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1111\/j.1365-2958.2008.06413.x","article-title":"Polymorphisms within PfMDR1 alter the substrate specificity for anti-malarial drugs in Plasmodium Falciparum","volume":"70","author":"Sanchez","year":"2008","journal-title":"Mol. Microbiol."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Simon, N., Voigtl\u00e4nder, C., Kappes, B., Rohrbach, P., and Friedrich, O. (2022). PfMDR1 transport rates assessed in Intact Isolated Plasmodium falciparum digestive vacuoles reflect functional drug resistance relationship with pfmdr1 mutations. Pharmaceuticals, 15.","DOI":"10.3390\/ph15020202"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/S0166-6851(97)00062-5","article-title":"Generation of hemoglobin peptides in the acidic digestive vacuole of Plasmodium falciparum implicates peptide transport in amino acid production","volume":"87","author":"Kolakovich","year":"1997","journal-title":"Mol. Biochem. Parasitol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"5731","DOI":"10.1016\/S0021-9258(18)42611-7","article-title":"Peptide transport by the multidrug resistance pump","volume":"267","author":"Sharma","year":"1992","journal-title":"J. Biol. Chem."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1111\/j.1432-1033.1994.tb18928.x","article-title":"Probing the interaction of the multidrug resistance phenotype with the polypeptide ionophore gramicidin D via functional channel formation","volume":"222","author":"Assaraf","year":"1994","journal-title":"Eur. J. Biochem."},{"key":"ref_80","first-page":"1779","article-title":"Multidrug resistance phenotype of human BRO melanoma cells transfected with a wild-type human mdr1 complementary DNA","volume":"50","author":"Lincke","year":"1990","journal-title":"Cancer Res."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1124\/mol.54.1.170","article-title":"Access to hematin: The basis of chloroquine resistance","volume":"54","author":"Bray","year":"1998","journal-title":"Mol. Pharmacol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1046\/j.1472-8206.2003.00164.x","article-title":"The mechanisms of resistance to antimalarial drugs in Plasmodium falciparum","volume":"17","author":"Durand","year":"2003","journal-title":"Fundam. Clin. Pharmacol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1083\/jcb.140.2.335","article-title":"Differential stimulation of the Na+\/H+ exchanger determines chloroquine uptake in Plasmodium falciparum","volume":"140","author":"Sanchez","year":"1998","journal-title":"J. Cell Biol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/S0006-2952(98)00140-3","article-title":"Role for the Plasmodium falciparum digestive vacuole in chloroquine resistance","volume":"56","author":"Saliba","year":"1998","journal-title":"Biochem. Pharmacol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1016\/S0035-9203(97)90110-3","article-title":"An alternative to serum for cultivation of Plasmodium falciparum in vitro","volume":"91","author":"Cranmer","year":"1997","journal-title":"Trans. R. Soc. Trop. Med. Hyg."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1126\/science.781840","article-title":"Human malaria parasites in continuous culture","volume":"193","author":"Trager","year":"1976","journal-title":"Science"},{"key":"ref_87","unstructured":"Makowa, H.B. (2012). The Relationship between the Insecticide Dichloro-Diphenyl-Trichloroethane and Chloroquine in Plasmodium falciparum Resistance. [Master\u2019s Thesis, University of Stellenbosch]. Available online: http:\/\/scholar.sun.ac.za\/handle\/10019.1\/20310?show=full."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"418","DOI":"10.2307\/3280287","article-title":"Synchronization of Plasmodium falciparum erythrocytic stages in culture","volume":"65","author":"Lambros","year":"1979","journal-title":"J. Parasitol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"760","DOI":"10.4269\/ajtmh.1975.24.760","article-title":"Protein synthesis in vitro by cryopreserved Plasmodium Falciparum","volume":"24","author":"Diggs","year":"1975","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1111\/j.1365-2257.1997.tb00001.x","article-title":"The laboratory diagnosis of malaria","volume":"2","author":"Reilly","year":"1997","journal-title":"Clin. Lab. Haematol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1128\/CMR.15.3.355-364.2002","article-title":"Cultivation of Plasmodium spp.","volume":"15","author":"Schuster","year":"2002","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1111\/cbdd.12344","article-title":"SAR and PCA analysis of the tyrocidines towards leucocin A sensitive and resistant Listeria monocytogenes","volume":"84","author":"Leussa","year":"2014","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.4269\/ajtmh.2007.76.1107","article-title":"In vitro antimalarial susceptibility profile and pfcrt\/pfmdr-1 genotypes of Plasmodium falciparum field isolates from Malawi","volume":"76","author":"Nkhoma","year":"2007","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/S0166-6851(97)00140-0","article-title":"Vander. Substrate and cofactor specificity and selective inhibition of lactate dehydrogenase from the malarial parasite P. falciparum","volume":"90","author":"Gomez","year":"1997","journal-title":"Mol. Biochem. Parasitol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.jsbmb.2011.11.003","article-title":"The influence of Aspalathus linearis Rooibos and dihydrochalcones on adrenal steroidogenesis: Quantification of steroid intermediates and end products in H295R cells","volume":"128","author":"Schloms","year":"2012","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.ab.2005.11.027","article-title":"Analyses of dose-response curves to compare the antimicrobial activity of model cationic alpha-helical peptides highlights the necessity for a minimum of two activity parameters","volume":"350","author":"Rautenbach","year":"2006","journal-title":"Anal. Biochem."},{"key":"ref_97","first-page":"1","article-title":"The effect of artemisinin combined with standard antimalarials against chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum in vitro","volume":"90","author":"Chawira","year":"1987","journal-title":"J. Trop. Med. Hyg."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"4097","DOI":"10.1128\/AAC.48.11.4097-4102.2004","article-title":"Modified fixed-ratio isobologram method for studying in vitro interactions between atovaquone and proguanil or dihydroartemisinin against drug-resistant strains of Plasmodium Falciparum","volume":"48","author":"Fivelman","year":"2004","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.femsle.2005.09.035","article-title":"Antimalarial drug synergism and antagonism: Mechanistic and clinical significance","volume":"253","author":"Bell","year":"2005","journal-title":"FEMS Microbiol. Lett."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/jac\/dkg301","article-title":"Synergy, antagonism, what the chequerboard puts between them","volume":"52","author":"Odds","year":"2003","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1510","DOI":"10.1128\/AAC.46.5.1510-1515.2002","article-title":"In vitro interactions of artemisinin with atovaquone, quinine, mefloquine against Plasmodium falciparum","volume":"46","author":"Gupta","year":"2002","journal-title":"Antimicrob. Agents Chemother."}],"container-title":["Antibiotics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-6382\/11\/6\/801\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:31:26Z","timestamp":1760139086000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-6382\/11\/6\/801"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,14]]},"references-count":101,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2022,6]]}},"alternative-id":["antibiotics11060801"],"URL":"https:\/\/doi.org\/10.3390\/antibiotics11060801","relation":{},"ISSN":["2079-6382"],"issn-type":[{"value":"2079-6382","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,14]]}}}