{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T21:09:18Z","timestamp":1791234558885,"version":"4.1.0"},"reference-count":31,"publisher":"American Society for Microbiology","issue":"5","license":[{"start":{"date-parts":[[2014,5,1]],"date-time":"2014-05-01T00:00:00Z","timestamp":1398902400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2014,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Leishmania donovani<\/jats:named-content>\n            is the causative agent of the potentially fatal disease visceral leishmaniasis (VL). Chemotherapeutic options available to treat VL are limited and often face parasite resistance, inconsistent efficacy, and toxic side effects. Paromomycin (PMM) was recently introduced to treat VL as a monotherapy and in combination therapy. It is vital to understand the mechanisms of PMM resistance to safeguard the drug. In the present study, we utilized experimentally generated PMM-resistant\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">L. donovani<\/jats:named-content>\n            to elucidate the mechanisms of resistance and parasite biology. We found increased membrane fluidity accompanied by decreased intracellular drug accumulation in the PMM-resistant parasites. There were marked increases in gene expression of ATP-binding cassette (ABC) transporters (MDR1 and MRPA) and protein phosphatase 2A that evince increased drug efflux. Further, evaluation of parasite tolerance toward host leishmanicidal mechanisms revealed PMM-resistant parasites as being more tolerant to nitrosative stress at the promastigote and amastigote stages. The PMM-resistant parasites also predicted a better survival capacity, as indicated by resistance to complement-mediated lysis and increased stimulation of host interleukin-10 (IL-10) expression. The susceptibilities of PMM-resistant isolates to other antileishmanial agents (sodium antimony gluconate and miltefosine) remained unchanged. The data implicated the roles of altered membrane fluidity, decreased drug accumulation, increased expression of ABC transporters, and greater tolerance of parasites to host defense mechanisms in conferring PMM resistance in\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Leishmania<\/jats:named-content>\n            .\n          <\/jats:p>","DOI":"10.1128\/aac.01574-13","type":"journal-article","created":{"date-parts":[[2014,2,19]],"date-time":"2014-02-19T05:16:41Z","timestamp":1392787001000},"page":"2580-2585","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":68,"title":["Elucidation of Cellular Mechanisms Involved in Experimental Paromomycin Resistance in Leishmania donovani"],"prefix":"10.1128","volume":"58","author":[{"given":"Vasundhra","family":"Bhandari","sequence":"first","affiliation":[{"name":"National Institute of Pathology, Indian Council of Medical Research, Safdarjung Hospital Campus, New Delhi, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shyam","family":"Sundar","sequence":"additional","affiliation":[{"name":"Institute of Medical Sciences, Banaras Hindu University, Varanasi, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean Claude","family":"Dujardin","sequence":"additional","affiliation":[{"name":"Unit of Molecular Parasitology, Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium"},{"name":"Department of Biomedical Sciences, Faculty of Pharmaceutical, Biomedical, and Veterinary Sciences, University of Antwerp, Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Poonam","family":"Salotra","sequence":"additional","affiliation":[{"name":"National Institute of Pathology, Indian Council of Medical Research, Safdarjung Hospital Campus, New Delhi, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(02)00347-X"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0035671"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1086\/318121"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0903627"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0001657"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cis474"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cit102"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1155\/2011\/645203"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1097\/QCO.0b013e32833fca9d"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(10)62050-8"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00812-10"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1989.tb03494.x"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.7164\/antibiotics.21.458"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molbiopara.2008.12.007"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1007\/s004360050232"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1051\/parasite\/1998052167"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0001664"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2010.03.012"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpara.2011.07.013"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00436-012-2823-z"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1017\/S0031182007003782"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0012211"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1017\/S0031182005008486"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1017\/S0031182011001120"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.20.14865"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00030-11"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1128\/EC.00152-06"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00436-007-0701-x"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0000904"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.68.1.288-293.2000"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1213839110"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.01574-13","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.01574-13","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,21]],"date-time":"2022-02-21T22:38:48Z","timestamp":1645483128000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/AAC.01574-13"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,5]]},"references-count":31,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2014,5]]}},"alternative-id":["10.1128\/AAC.01574-13"],"URL":"https:\/\/doi.org\/10.1128\/aac.01574-13","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,5]]},"assertion":[{"value":"2013-07-19","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2014-02-08","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2014-04-10","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}