{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T07:21:17Z","timestamp":1793085677327,"version":"4.5.0"},"update-to":[{"DOI":"10.1371\/journal.pntd.0013837","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T00:00:00Z","timestamp":1766102400000}}],"reference-count":84,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T00:00:00Z","timestamp":1765843200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["R01AI141439"],"award-info":[{"award-number":["R01AI141439"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosntds.org"],"crossmark-restriction":false},"short-container-title":["PLoS Negl Trop Dis"],"abstract":"<jats:p>\n                    Cryptococcosis is an opportunistic fungal infection affecting individuals with compromised immunity, particularly those with HIV. The limited accessibility to effective treatments and treatment-related toxicities underline the need for more effective therapeutic options. In this study, we conducted a whole-cell screening of ~ 3,700 FDA-approved drugs and clinical molecules against the\n                    <jats:italic>Cryptococcus neoformans<\/jats:italic>\n                    H99 strain. The anti-mycobacterial agent SQ109 was identified as one of the most potent hits, with broad antifungal activity. SQ109 exhibited potent activity against\n                    <jats:italic>Cryptococcus<\/jats:italic>\n                    spp\n                    <jats:italic>.<\/jats:italic>\n                    , with an MIC90 of 4 \u03bcg\/mL. In the time-kill assay, SQ109 demonstrated a fungicidal activity on proliferating cryptococcal cells in a concentration-dependent manner. Unlike fluconazole (FLC) and flucytosine (5-FC),\n                    <jats:italic>C. neoformans<\/jats:italic>\n                    showed a negligible tendency to develop resistance to SQ109 during frequent passaging. Furthermore, SQ109 exhibited a potent efficiency in the murine model of cryptococcal infection, resulting in a 50% survival rate among animals treated with 25 mg\/kg for 10 consecutive days. The transcriptomic analysis revealed that SQ109 disrupts ergosterol biosynthesis, affecting membrane integrity and oxidative homeostasis. Additionally, molecular docking and structural analysis indicated that squalene synthase protein ERG9 is the most likely target of SQ109 within the ergosterol biosynthesis machinery of cryptococcal cells. Notably, SQ109 potentiates the activity of the standard antifungal FLC, as well as other ergosterol inhibitors, with a fractional inhibitory concentration Index (\u03a3FICI) ranging from 0.38 to 1. These findings highlight the therapeutic potential of SQ109 in combating cryptococcal infections, both as a standalone therapy and as an adjuvant to FLC monotherapy.\n                  <\/jats:p>","DOI":"10.1371\/journal.pntd.0013837","type":"journal-article","created":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T18:35:27Z","timestamp":1765910127000},"page":"e0013837","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["In vitro and in vivo efficacy of the antimycobacterial molecule SQ109 against the human pathogenic fungus, Cryptococcus neoformans"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-0632-3747","authenticated-orcid":true,"given":"Nour M.","family":"Alkashef","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ehab A.","family":"Salama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramu","family":"Anandakrishnan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tony R.","family":"Hazbun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Micah V.","family":"Hoernig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne M.","family":"Brown","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher B.","family":"Lawrence","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0939-0458","authenticated-orcid":true,"given":"Mohamed N.","family":"Seleem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,12,16]]},"reference":[{"issue":"12","key":"pntd.0013837.ref001","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.1007\/s40265-022-01757-5","article-title":"Treatment of cryptococcal meningitis: how have we got here and where are we going?","volume":"82","author":"NTT Ngan","year":"2022","journal-title":"Drugs"},{"issue":"1","key":"pntd.0013837.ref002","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1080\/21505594.2019.1614383","article-title":"Basic principles of the virulence of Cryptococcus","volume":"10","author":"O Zaragoza","year":"2019","journal-title":"Virulence"},{"key":"pntd.0013837.ref003","doi-asserted-by":"crossref","first-page":"657502","DOI":"10.3389\/fcimb.2021.657502","article-title":"Cryptococcal Virulence in Humans: Learning From Translational Studies With Clinical Isolates","volume":"11","author":"HR de Sousa","year":"2021","journal-title":"Front Cell Infect Microbiol"},{"issue":"12","key":"pntd.0013837.ref004","doi-asserted-by":"crossref","first-page":"1748","DOI":"10.1016\/S1473-3099(22)00499-6","article-title":"The global burden of HIV-associated cryptococcal infection in adults in 2020: a modelling analysis","volume":"22","author":"R Rajasingham","year":"2022","journal-title":"Lancet Infect Dis"},{"issue":"7","key":"pntd.0013837.ref005","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1038\/s41579-021-00511-0","article-title":"Treatment strategies for cryptococcal infection: challenges, advances and future outlook","volume":"19","author":"KR Iyer","year":"2021","journal-title":"Nat Rev Microbiol"},{"issue":"4","key":"pntd.0013837.ref006","doi-asserted-by":"crossref","DOI":"10.1128\/cmr.00156-22","article-title":"Diagnosis and management of cryptococcal meningitis in HIV-infected adults","volume":"36","author":"TC McHale","year":"2023","journal-title":"Clin Microbiol Rev"},{"issue":"8","key":"pntd.0013837.ref007","doi-asserted-by":"crossref","DOI":"10.1016\/S1473-3099(23)00731-4","article-title":"Global guideline for the diagnosis and management of cryptococcosis: an initiative of the ECMM and ISHAM in cooperation with the ASM","volume":"24","author":"CC Chang","year":"2024","journal-title":"Lancet Infect Dis"},{"issue":"10","key":"pntd.0013837.ref008","doi-asserted-by":"crossref","DOI":"10.1093\/ofid\/ofz369","article-title":"Minimum Inhibitory Concentration Distribution of Fluconazole against Cryptococcus Species and the Fluconazole Exposure Prediction Model","volume":"6","author":"S Chesdachai","year":"2019","journal-title":"Open Forum Infect Dis"},{"issue":"12","key":"pntd.0013837.ref009","doi-asserted-by":"crossref","first-page":"1556","DOI":"10.1086\/593194","article-title":"Dose response effect of high-dose fluconazole for HIV-associated cryptococcal meningitis in southwestern Uganda","volume":"47","author":"N Longley","year":"2008","journal-title":"Clin Infect Dis"},{"issue":"3","key":"pntd.0013837.ref010","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1086\/649861","article-title":"Combination flucytosine and high-dose fluconazole compared with fluconazole monotherapy for the treatment of cryptococcal meningitis: a randomized trial in Malawi","volume":"50","author":"JC Nussbaum","year":"2010","journal-title":"Clin Infect Dis"},{"issue":"4","key":"pntd.0013837.ref011","doi-asserted-by":"crossref","first-page":"613","DOI":"10.3390\/microorganisms8040613","article-title":"New Approaches for Cryptococcosis Treatment","volume":"8","author":"C Spadari C de","year":"2020","journal-title":"Microorganisms"},{"key":"pntd.0013837.ref012","article-title":"Searching for new antifungals for the treatment of cryptococcosis","volume":"56","author":"NSO de Sousa","year":"2023","journal-title":"Rev Soc Bras Med Trop"},{"issue":"7","key":"pntd.0013837.ref013","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1016\/j.jacbts.2019.10.008","article-title":"Limitations of Animal Studies for Predicting Toxicity in Clinical Trials: Is it Time to Rethink Our Current Approach?","volume":"4","author":"GA Van Norman","year":"2019","journal-title":"JACC Basic Transl Sci"},{"issue":"6","key":"pntd.0013837.ref014","doi-asserted-by":"crossref","first-page":"1662","DOI":"10.1021\/acsinfecdis.5c00210","article-title":"Broad-Spectrum Activity and Mechanisms of Action of SQ109 on a Variety of Fungi","volume":"11","author":"SR Malwal","year":"2025","journal-title":"ACS Infect Dis"},{"issue":"5","key":"pntd.0013837.ref015","doi-asserted-by":"crossref","first-page":"1558","DOI":"10.1093\/jac\/dku553","article-title":"Early phase evaluation of SQ109 alone and in combination with rifampicin in pulmonary TB patients","volume":"70","author":"N Heinrich","year":"2015","journal-title":"J Antimicrob Chemother"},{"issue":"3","key":"pntd.0013837.ref016","first-page":"6","article-title":"Efficiency and safety of chemotherapy regimen with sq109 in those suffering from multiple drug resistant tuberculosis","volume":"96","author":"SE Borisov","year":"2018","journal-title":"Tabercul Lung Dis"},{"issue":"1","key":"pntd.0013837.ref017","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1038\/sj.bjp.0705984","article-title":"Pharmacodynamics and pharmacokinetics of SQ109, a new diamine-based antitubercular drug","volume":"144","author":"L Jia","year":"2005","journal-title":"Br J Pharmacol"},{"issue":"5","key":"pntd.0013837.ref018","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1038\/sj.bjp.0706650","article-title":"Interspecies pharmacokinetics and in vitro metabolism of SQ109","volume":"147","author":"L Jia","year":"2006","journal-title":"Br J Pharmacol"},{"issue":"9","key":"pntd.0013837.ref019","doi-asserted-by":"crossref","DOI":"10.1128\/AAC.00024-21","article-title":"Pharmacokinetics and Target Attainment of SQ109 in Plasma and Human-Like Tuberculosis Lesions in Rabbits","volume":"65","author":"O Egbelowo","year":"2021","journal-title":"Antimicrob Agents Chemother"},{"issue":"3","key":"pntd.0013837.ref020","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.tube.2010.03.003","article-title":"Tuberculosis drug development: progress, challenges, and the road ahead","volume":"90","author":"AM Ginsberg","year":"2010","journal-title":"Tuberculosis (Edinb)"},{"issue":"12","key":"pntd.0013837.ref021","doi-asserted-by":"crossref","first-page":"13782","DOI":"10.1021\/acsomega.3c08401","article-title":"Novel Inhibitors to MmpL3 Transporter of Mycobacterium tuberculosis by Structure-Based High-Throughput Virtual Screening and Molecular Dynamics Simulations","volume":"9","author":"H Choksi","year":"2024","journal-title":"ACS Omega"},{"issue":"1","key":"pntd.0013837.ref022","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/S1473-3099(16)30274-2","article-title":"High-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: a multi-arm, multi-stage randomised controlled trial","volume":"17","author":"MJ Boeree","year":"2017","journal-title":"Lancet Infect Dis"},{"issue":"1","key":"pntd.0013837.ref023","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1038\/s42003-022-03693-2","article-title":"The 1, 2-ethylenediamine SQ109 protects against tuberculosis by promoting M1 macrophage polarization through the p38 MAPK pathway","volume":"5","author":"M Singh","year":"2022","journal-title":"Commun Biol"},{"issue":"4","key":"pntd.0013837.ref024","doi-asserted-by":"crossref","first-page":"1950","DOI":"10.1128\/AAC.03972-14","article-title":"SQ109, a new drug lead for Chagas disease","volume":"59","author":"P Veiga-Santos","year":"2015","journal-title":"Antimicrob Agents Chemother"},{"issue":"7","key":"pntd.0013837.ref025","doi-asserted-by":"crossref","first-page":"3126","DOI":"10.1021\/jm500131s","article-title":"Multitarget drug discovery for tuberculosis and other infectious diseases","volume":"57","author":"K Li","year":"2014","journal-title":"J Med Chem"},{"issue":"8016","key":"pntd.0013837.ref026","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1038\/s41586-024-07487-w","article-title":"Accurate structure prediction of biomolecular interactions with AlphaFold 3","volume":"630","author":"J Abramson","year":"2024","journal-title":"Nature"},{"issue":"10","key":"pntd.0013837.ref027","doi-asserted-by":"crossref","first-page":"3865","DOI":"10.1073\/pnas.1324245111","article-title":"Architecture of a single membrane spanning cytochrome P450 suggests constraints that orient the catalytic domain relative to a bilayer","volume":"111","author":"BC Monk","year":"2014","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"pntd.0013837.ref028","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1186\/s13321-021-00522-2","article-title":"GNINA 1.0: molecular docking with deep learning","volume":"13","author":"AT McNutt","year":"2021","journal-title":"J Cheminform"},{"key":"pntd.0013837.ref029","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkae1010","article-title":"UniProt: the Universal Protein Knowledgebase in 2025","volume":"53","author":"UniProt Consortium","year":"2025","journal-title":"Nucleic Acids Res"},{"key":"pntd.0013837.ref030","doi-asserted-by":"crossref","first-page":"106228","DOI":"10.1016\/j.actatropica.2021.106228","article-title":"Cryptococcal meningitis in patients with and without acquired immunodeficiency","volume":"227","author":"YdO Ohnishi","year":"2022","journal-title":"Acta Trop"},{"key":"pntd.0013837.ref031","volume-title":"WHO fungal priority pathogens list to guide research, development and public healthaction","author":"World Health organization (WHO)","year":"2022"},{"issue":"5","key":"pntd.0013837.ref032","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1016\/j.jmii.2010.08.011","article-title":"Comparisons of clinical features and mortality of cryptococcal meningitis between patients with and without human immunodeficiency virus infection","volume":"44","author":"Y-C Lee","year":"2011","journal-title":"J Microbiol Immunol Infect"},{"issue":"1","key":"pntd.0013837.ref033","doi-asserted-by":"crossref","first-page":"9387","DOI":"10.1038\/s41598-020-66094-7","article-title":"Clinical analysis in immunocompetent and immunocompromised patients with pulmonary cryptococcosis in western China","volume":"10","author":"J Qu","year":"2020","journal-title":"Sci Rep"},{"key":"pntd.0013837.ref034","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.mmcr.2013.11.003","article-title":"Cryptococcal infection in non-HIV immunosuppressed patients - Three case reports in a nephrology setting","volume":"3","author":"P Ventura Aguiar","year":"2013","journal-title":"Med Mycol Case Rep"},{"key":"pntd.0013837.ref035","first-page":"20499361241232851","article-title":"COVID-19 associated with cryptococcosis: a scoping review","volume":"11","author":"A Quincho-Lopez","year":"2024","journal-title":"Ther Adv Infect Dis"},{"issue":"8","key":"pntd.0013837.ref036","doi-asserted-by":"crossref","DOI":"10.1093\/ofid\/ofad420","article-title":"Cryptococcal Meningitis in Young, Immunocompetent Patients: A Single-Center Retrospective Case Series and Review of the Literature","volume":"10","author":"M Stack","year":"2023","journal-title":"Open Forum Infect Dis"},{"issue":"4","key":"pntd.0013837.ref037","article-title":"Antifungal drugs: special problems treating central nervous system infections","volume":"5","author":"ED Ashley","year":"2019","journal-title":"J Fungi (Basel)"},{"issue":"4","key":"pntd.0013837.ref038","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1517\/17425255.3.4.573","article-title":"CNS pharmacokinetics of antifungal agents","volume":"3","author":"S Kethireddy","year":"2007","journal-title":"Expert Opin Drug Metab Toxicol"},{"issue":"2","key":"pntd.0013837.ref039","doi-asserted-by":"crossref","DOI":"10.1128\/spectrum.04783-22","article-title":"Carbon Dioxide Potentiates Flucytosine Susceptibility in Cryptococcus neoformans","volume":"11","author":"AJ Jezewski","year":"2023","journal-title":"Microbiol Spectr"},{"issue":"4","key":"pntd.0013837.ref040","doi-asserted-by":"crossref","DOI":"10.1128\/mBio.01410-19","article-title":"Host Carbon Dioxide Concentration Is an Independent Stress for Cryptococcus neoformans That Affects Virulence and Antifungal Susceptibility","volume":"10","author":"DJ Krysan","year":"2019","journal-title":"mBio"},{"issue":"4","key":"pntd.0013837.ref041","doi-asserted-by":"crossref","first-page":"1797","DOI":"10.1128\/AAC.05708-11","article-title":"SQ109 targets MmpL3, a membrane transporter of trehalose monomycolate involved in mycolic acid donation to the cell wall core of Mycobacterium tuberculosis","volume":"56","author":"K Tahlan","year":"2012","journal-title":"Antimicrob Agents Chemother"},{"issue":"7","key":"pntd.0013837.ref042","doi-asserted-by":"crossref","first-page":"823","DOI":"10.2217\/fmb.12.56","article-title":"Discovery and development of SQ109: a new antitubercular drug with a novel mechanism of action","volume":"7","author":"KA Sacksteder","year":"2012","journal-title":"Future Microbiol"},{"key":"pntd.0013837.ref043","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1186\/1471-2180-11-97","article-title":"Genome-wide expression profiling of the response to short-term exposure to fluconazole in Cryptococcus neoformans serotype A","volume":"11","author":"AR Florio","year":"2011","journal-title":"BMC Microbiol"},{"issue":"4","key":"pntd.0013837.ref044","doi-asserted-by":"crossref","DOI":"10.1128\/mBio.01291-18","article-title":"Overexpression or deletion of ergosterol biosynthesis genes alters doubling time, response to stress agents, and drug susceptibility in Saccharomyces cerevisiae","volume":"9","author":"S Bhattacharya","year":"2018","journal-title":"mBio"},{"issue":"9","key":"pntd.0013837.ref045","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0139306","article-title":"Changes in the sterol composition of the plasma membrane affect membrane potential, salt tolerance and the activity of multidrug resistance pumps in Saccharomyces cerevisiae","volume":"10","author":"M Kodedov\u00e1","year":"2015","journal-title":"PLoS One"},{"key":"pntd.0013837.ref046","doi-asserted-by":"crossref","first-page":"103368","DOI":"10.1016\/j.fgb.2020.103368","article-title":"Erg6 affects membrane composition and virulence of the human fungal pathogen Cryptococcus neoformans","volume":"140","author":"FFM Oliveira","year":"2020","journal-title":"Fungal Genet Biol"},{"issue":"1","key":"pntd.0013837.ref047","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.funbio.2021.09.002","article-title":"Ergosterol depletion under bifonazole treatment induces cell membrane damage and triggers a ROS-mediated mitochondrial apoptosis in Penicillium expansum","volume":"126","author":"S Yang","year":"2022","journal-title":"Fungal Biol"},{"issue":"1","key":"pntd.0013837.ref048","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1186\/s12866-019-1606-4","article-title":"Increase of reactive oxygen species contributes to growth inhibition by fluconazole in Cryptococcus neoformans","volume":"19","author":"NH Dbouk","year":"2019","journal-title":"BMC Microbiol"},{"issue":"5","key":"pntd.0013837.ref049","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1038\/s41564-024-01662-5","article-title":"A dual-targeting antifungal is effective against multidrug-resistant human fungal pathogens","volume":"9","author":"M Zhou","year":"2024","journal-title":"Nat Microbiol"},{"issue":"12","key":"pntd.0013837.ref050","article-title":"Fluconazole induces ROS in Cryptococcus neoformans and contributes to DNA damage in vitro","volume":"13","author":"CA Peng","year":"2018","journal-title":"PLoS One"},{"issue":"7","key":"pntd.0013837.ref051","doi-asserted-by":"crossref","DOI":"10.1128\/mbio.01031-24","article-title":"Brilacidin, a novel antifungal agent against Cryptococcus neoformans","volume":"15","author":"C Diehl","year":"2024","journal-title":"mBio"},{"issue":"6","key":"pntd.0013837.ref052","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1128\/EC.3.6.1391-1397.2004","article-title":"Role of Candida albicans transcription factor Upc2p in drug resistance and sterol metabolism","volume":"3","author":"PM Silver","year":"2004","journal-title":"Eukaryot Cell"},{"issue":"5","key":"pntd.0013837.ref053","doi-asserted-by":"crossref","first-page":"1745","DOI":"10.1128\/AAC.49.5.1745-1752.2005","article-title":"Candida albicans zinc cluster protein Upc2p confers resistance to antifungal drugs and is an activator of ergosterol biosynthetic genes","volume":"49","author":"S MacPherson","year":"2005","journal-title":"Antimicrob Agents Chemother"},{"key":"pntd.0013837.ref054","doi-asserted-by":"crossref","first-page":"6129","DOI":"10.1038\/ncomms7129","article-title":"Structural mechanism of ergosterol regulation by fungal sterol transcription factor Upc2","volume":"6","author":"H Yang","year":"2015","journal-title":"Nat Commun"},{"issue":"26","key":"pntd.0013837.ref055","doi-asserted-by":"crossref","first-page":"22601","DOI":"10.1021\/acsomega.2c01924","article-title":"A Structural and Bioinformatics Investigation of a Fungal Squalene Synthase and Comparisons with Other Membrane Proteins","volume":"7","author":"SR Malwal","year":"2022","journal-title":"ACS Omega"},{"key":"pntd.0013837.ref056","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/S0079-6603(00)65005-5","article-title":"Squalene synthase: structure and regulation","volume":"65","author":"TR Tansey","year":"2001","journal-title":"Prog Nucleic Acid Res Mol Biol"},{"issue":"4","key":"pntd.0013837.ref057","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1000848","article-title":"Cryptococcus neoformans overcomes stress of azole drugs by formation of disomy in specific multiple chromosomes","volume":"6","author":"E Sionov","year":"2010","journal-title":"PLoS Pathog"},{"issue":"1","key":"pntd.0013837.ref058","doi-asserted-by":"crossref","first-page":"3418","DOI":"10.1038\/s41467-021-23745-1","article-title":"Moderate levels of 5-fluorocytosine cause the emergence of high frequency resistance in cryptococci","volume":"12","author":"YC Chang","year":"2021","journal-title":"Nat Commun"},{"issue":"1","key":"pntd.0013837.ref059","doi-asserted-by":"crossref","first-page":"1968","DOI":"10.1038\/s41467-017-02126-7","article-title":"Galectin-3 impacts Cryptococcus neoformans infection through direct antifungal effects","volume":"8","author":"F Almeida","year":"2017","journal-title":"Nat Commun"},{"issue":"8","key":"pntd.0013837.ref060","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0308216","article-title":"Novel combinatorial approach: Harnessing HIV protease inhibitors to enhance amphotericin B\u2019s antifungal efficacy in cryptococcosis","volume":"19","author":"NM Alkashef","year":"2024","journal-title":"PLoS One"},{"key":"pntd.0013837.ref061","volume-title":"Reference method for broth dilution antifungal susceptibility testing of yeasts; approved standard, 3rd ed. CLSI document M27-A3","author":"CLSI","year":"2008"},{"key":"pntd.0013837.ref062","volume-title":"Reference method for broth dilution antifungal susceptibility testing of filamentous fungi; approved standard, 2nd ed. CLSI document M38-A2","author":"CLSI","year":"2008"},{"key":"pntd.0013837.ref063","doi-asserted-by":"crossref","first-page":"535","DOI":"10.3389\/fmicb.2017.00535","article-title":"The Anti-helminthic Compound Mebendazole Has Multiple Antifungal Effects against Cryptococcus neoformans","volume":"8","author":"LS Joffe","year":"2017","journal-title":"Front Microbiol"},{"issue":"11","key":"pntd.0013837.ref064","doi-asserted-by":"crossref","DOI":"10.1128\/aac.00556-24","article-title":"Overcoming amphotericin B resistance in Candida auris using the antiemetic drug rolapitant","volume":"68","author":"EA Salama","year":"2024","journal-title":"Antimicrob Agents Chemother"},{"issue":"7","key":"pntd.0013837.ref065","doi-asserted-by":"crossref","first-page":"3758","DOI":"10.1128\/AAC.00212-12","article-title":"The antidepressant sertraline provides a promising therapeutic option for neurotropic cryptococcal infections","volume":"56","author":"B Zhai","year":"2012","journal-title":"Antimicrob Agents Chemother"},{"issue":"4","key":"pntd.0013837.ref066","doi-asserted-by":"crossref","DOI":"10.1128\/AAC.01921-19","article-title":"Identification of Off-Patent Drugs That Show Synergism with Amphotericin B or That Present Antifungal Action against Cryptococcus neoformans and Candida spp","volume":"64","author":"SA Rossi","year":"2020","journal-title":"Antimicrob Agents Chemother"},{"issue":"1","key":"pntd.0013837.ref067","doi-asserted-by":"crossref","first-page":"2322649","DOI":"10.1080\/22221751.2024.2322649","article-title":"Lansoprazole interferes with fungal respiration and acts synergistically with amphotericin B against multidrug-resistant Candida auris","volume":"13","author":"EA Salama","year":"2024","journal-title":"Emerg Microbes Infect"},{"issue":"17","key":"pntd.0013837.ref068","doi-asserted-by":"crossref","DOI":"10.1093\/bioinformatics\/bty560","article-title":"fastp: an ultra-fast all-in-one FASTQ preprocessor","volume":"34","author":"S Chen","year":"2018","journal-title":"Bioinformatics"},{"issue":"4","key":"pntd.0013837.ref069","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgen.1004261","article-title":"Analysis of the genome and transcriptome of Cryptococcus neoformans var. grubii reveals complex RNA expression and microevolution leading to virulence attenuation","volume":"10","author":"G Janbon","year":"2014","journal-title":"PLoS Genet"},{"issue":"8","key":"pntd.0013837.ref070","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1038\/s41587-019-0201-4","article-title":"Graph-based genome alignment and genotyping with HISAT2 and HISAT-genotype","volume":"37","author":"D Kim","year":"2019","journal-title":"Nat Biotechnol"},{"issue":"10","key":"pntd.0013837.ref071","doi-asserted-by":"crossref","first-page":"2943","DOI":"10.1093\/bioinformatics\/btac166","article-title":"Analysing high-throughput sequencing data in Python with HTSeq 2.0","volume":"38","author":"GH Putri","year":"2022","journal-title":"Bioinformatics"},{"issue":"7","key":"pntd.0013837.ref072","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkv007","article-title":"limma powers differential expression analyses for RNA-sequencing and microarray studies","volume":"43","author":"ME Ritchie","year":"2015","journal-title":"Nucleic Acids Res"},{"key":"pntd.0013837.ref073","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkae270","article-title":"The structure assessment web server: for proteins, complexes and more","volume":"52","author":"AM Waterhouse","year":"2024","journal-title":"Nucleic Acids Res"},{"key":"pntd.0013837.ref074","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkm290","article-title":"ProSA-web: interactive web service for the recognition of errors in three-dimensional structures of proteins","volume":"35","author":"M Wiederstein","year":"2007","journal-title":"Nucleic Acids Res"},{"issue":"5016","key":"pntd.0013837.ref075","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1126\/science.1853201","article-title":"A method to identify protein sequences that fold into a known three-dimensional structure","volume":"253","author":"JU Bowie","year":"1991","journal-title":"Science"},{"issue":"1","key":"pntd.0013837.ref076","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1038\/s41467-018-07928-x","article-title":"Structure and inhibition mechanism of the catalytic domain of human squalene epoxidase","volume":"10","author":"AK Padyana","year":"2019","journal-title":"Nat Commun"},{"issue":"3","key":"pntd.0013837.ref077","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/S0022-2836(02)00470-9","article-title":"On the role of the crystal environment in determining protein side-chain conformations","volume":"320","author":"MP Jacobson","year":"2002","journal-title":"J Mol Biol"},{"issue":"2","key":"pntd.0013837.ref078","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.jmgm.2010.05.008","article-title":"Analysis and comparison of 2D fingerprints: insights into database screening performance using eight fingerprint methods","volume":"29","author":"J Duan","year":"2010","journal-title":"J Mol Graph Model"},{"issue":"8","key":"pntd.0013837.ref079","article-title":"Miltefosine Has a Postantifungal Effect and Induces Apoptosis in Cryptococcus Yeasts","volume":"62","author":"C Spadari C de","year":"2018","journal-title":"Antimicrob Agents Chemother"},{"issue":"1","key":"pntd.0013837.ref080","doi-asserted-by":"crossref","first-page":"5102","DOI":"10.1038\/s41467-018-07633-9","article-title":"Efflux pump-mediated resistance to antifungal compounds can be prevented by conjugation with triphenylphosphonium cation","volume":"9","author":"W Chang","year":"2018","journal-title":"Nat Commun"},{"issue":"4","key":"pntd.0013837.ref081","article-title":"Glucuronoxylomannan intranasal challenge prior to Cryptococcus neoformans pulmonary infection enhances cerebral cryptococcosis in rodents","volume":"19","author":"HH Lee","year":"2023","journal-title":"PLoS Pathog"},{"issue":"1","key":"pntd.0013837.ref082","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1080\/21505594.2017.1370529","article-title":"Na\u00efve B cells reduce fungal dissemination in Cryptococcus neoformans infected Rag1-\/- mice","volume":"9","author":"C Dufaud","year":"2018","journal-title":"Virulence"},{"issue":"4","key":"pntd.0013837.ref083","doi-asserted-by":"crossref","DOI":"10.1128\/mbio.03078-23","article-title":"Cryptococcus neoformans rapidly invades the murine brain by sequential breaching of airway and endothelial tissues barriers, followed by engulfment by microglia","volume":"15","author":"VI Francis","year":"2024","journal-title":"mBio"},{"key":"pntd.0013837.ref084","doi-asserted-by":"crossref","first-page":"21765","DOI":"10.1038\/srep21765","article-title":"Enhanced virulence of Histoplasma capsulatum through transfer and surface incorporation of glycans from Cryptococcus neoformans during co-infection","volume":"6","author":"RJB Cordero","year":"2016","journal-title":"Sci Rep"}],"updated-by":[{"DOI":"10.1371\/journal.pntd.0013837","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T00:00:00Z","timestamp":1766102400000}}],"container-title":["PLOS Neglected Tropical Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pntd.0013837","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T18:50:28Z","timestamp":1766170228000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pntd.0013837"}},"subtitle":[],"editor":[{"given":"Luis R","family":"Martinez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,12,16]]},"references-count":84,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,12,16]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pntd.0013837","relation":{},"ISSN":["1935-2735"],"issn-type":[{"value":"1935-2735","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,16]]}}}