In vivo evaluation of the antifungal activity of sertraline against Aspergillus fumigatus Rogelio de J. Trevi ~ no-Rangel 1 †, Hiram Villanueva-Lozano 1 †, Karen S. Me ´ndez-Galomo 1 , Elia M. Solı ´s-Villegas 1 , Miguel A. Becerril-Garcı ´a 1 , Alexandra M. Montoya 1 , Efre ´ n R. Robledo-Leal 2 and Gloria M. Gonza ´lez 1 * 1 Department of Microbiology, Faculty of Medicine, Universidad Auto ´ noma de Nuevo Leo ´ n, Monterrey, Mexico; 2 Faculty of Biological Sciences, Universidad Auto ´ noma de Nuevo Leo ´ n, San Nicola ´ s de los Garza, Mexico *Corresponding author. Tel: (!5281)-8329-4177; Fax: (!5281)-8348-5477; E-mail: gmglez@yahoo.com.mx †R. d. J. T.-R. and H. V.-L. contributed equally as first authors. Received 5 September 2018; returned 20 September 2018; revised 3 October 2018; accepted 5 October 2018 Background: Invasive pulmonary aspergillosis is a life-threatening fungal disease principally caused by the ubi- quitous mould Aspergillus fumigatus. This clinical entity is a major cause of morbidity and mortality (principally, but not restricted to, immunocompromised individuals). A few recent reports suggest in vitro fungicidal activity of sertraline against Aspergillus spp., but this activity has not yet been investigated in vivo. Objectives: To evaluate the antifungal activity of sertraline in two in vivo models of aspergillosis. Methods: The antifungal activity of sertraline as monotherapy at three different doses (3, 10 and 15 mg/kg) was evaluated in Galleria mellonella and in a murine model of invasive pulmonary aspergillosis. Therapeutic efficacy parameters determined were larval survival and health index score for G. mellonella, whereas pulmonary fungal burden, galactomannan and lung histopathology were assessed in the murine model. Results: Sertraline treatments improved larval survival and health index score, especially at doses of 10 and 15 mg/kg. Moreover, 10 mg/kg sertraline was able to reduce pulmonary fungal burden with an efficacy compar- able with that of 3 mg/kg amphotericin B and 10 mg/kg voriconazole. Conclusions: To the best of our knowledge, this is the first in vivo study that evaluates the antifungal activity of sertraline against A. fumigatus, showing a possible promising option for the adjuvant treatment of pulmonary aspergillosis. Introduction Invasive pulmonary aspergillosis (IPA) is an opportunistic fungal in- fection mainly originated by Aspergillus fumigatus through conidia inhalation. 1 The major risk factors are neutropenia and corticoster- oid therapy, 2 associated with mortality rates ranging from 35% to 80%. 1,3 The antifungal armamentarium is still limited, expensive and inaccessible in many cases. Drug ‘repurposing’ rep- resents a promising approach to discovering potential antifungal candidates. 4 Sertraline is a selective serotonin reuptake inhibitor commonly used as an antidepressant, 5 with some evidence of antifungal ac- tivity. 6 Although there are reports of in vitro fungicidal activity of sertraline against Aspergillus, 7–9 this property has not yet been corroborated in vivo, so the aim of this study was to evaluate this activity in two models of aspergillosis. Materials and methods Fungal strain The strain utilized was A. fumigatus CRCEI-16007, which was isolated from a bronchoalveolar lavage from an elderly Mexican patient with pneumonia. Strain identity was confirmed by sequencing of hydropho- bin (GenBank accession number: KX165404.1) and b-tubulin (GenBank accession number: KX165391.1) genes. 10 Antifungal susceptibility of the isolate was determined according to the CLSI broth microdilution method, 11 obtaining the following results: voriconazole MIC " 0.06 mg/L, amphotericin B MIC " 1 mg/L and sertraline MIC " 16 mg/L. For the inocula preparations used in the in vivo studies the strain was grown on potato dextrose agar (PDA) at 37  C for 7 days. Conidia were har- vested with 0.1% Tween 80 in saline and adjusted to the desired concentration. V C The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com. 663 J Antimicrob Chemother 2019; 74: 663–666 doi:10.1093/jac/dky455 Advance Access publication 6 November 2018 Downloaded from https://academic.oup.com/jac/article/74/3/663/5162960 by guest on 16 August 2022