000153225 001__ 153225
000153225 005__ 20251017144649.0
000153225 0247_ $$2doi$$a10.1128/spectrum.02332-24
000153225 0248_ $$2sideral$$a143652
000153225 037__ $$aART-2025-143652
000153225 041__ $$aeng
000153225 100__ $$0(orcid)0000-0001-9771-4912$$aEzquerra-Aznárez, José Manuel
000153225 245__ $$aThe emergence of resistance to the antiparasitic selamectin in Mycobacterium smegmatis is improbable and contingent on cell wall integrity
000153225 260__ $$c2025
000153225 5060_ $$aAccess copy available to the general public$$fUnrestricted
000153225 5203_ $$aTuberculosis remains the deadliest infectious disease of the 21st century. New antimicrobials are needed to improve treatment outcomes and enable therapy shortening. Drug repurposing is an alternative to the traditional drug discovery process. The avermectins are a family of macrocyclic lactones with anthelmintic activity active against Mycobacterium tuberculosis. However, their mode of action in mycobacteria remains unknown. In this study, we employed traditional mutant isolation approaches using Mycobacterium smegmatis, a non-pathogenic M. tuberculosis surrogate. We were only able to isolate mutants with decreased susceptibility to selamectin using the ∆nucS mutator M. smegmatis strain. This phenotype was caused by mutations in mps1 and mmpL11. Two of these mutants were used for a second experiment in which high-level selamectin-resistant mutants were isolated; however, specific mutations driving the phenotypic change to high-level resistance could not be identified. The susceptibility to selamectin in these mutants was restored to the basal level by subinhibitory concentrations of ethambutol. The selection of ethambutol resistance in a high-level selamectin-resistant mutant also resulted in multiple colonies becoming susceptible to selamectin again. These colonies carried mutations in embB, suggesting that the integrity of the cell envelope is a prerequisite for selamectin resistance. The absence of increased susceptibility to selamectin in an embB deletion strain demonstrated that the target of selamectin is not cytosolic. Our data show that the concurrence of specific multiple mutations and complete integrity of the mycobacterial envelope are necessary for selamectin resistance. Our studies provide first-time insights into the antimycobacterial mode of action of the antiparasitic avermectins.
000153225 536__ $$9info:eu-repo/grantAgreement/ES/MCIU/FPU18-03873
000153225 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttps://creativecommons.org/licenses/by/4.0/deed.es
000153225 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000153225 700__ $$aGašparovic, Henrich
000153225 700__ $$aChiner-Oms, Álvaro
000153225 700__ $$0(orcid)0000-0002-0111-4697$$aLucía, Ainhoa$$uUniversidad de Zaragoza
000153225 700__ $$aBlázquez, Jesús
000153225 700__ $$aComas, Iñaki
000153225 700__ $$aKorduláková, Jana
000153225 700__ $$0(orcid)0000-0003-2076-844X$$aAínsa, José A.$$uUniversidad de Zaragoza
000153225 700__ $$0(orcid)0000-0002-8480-0325$$aRamón-García, Santiago
000153225 7102_ $$11011$$2630$$aUniversidad de Zaragoza$$bDpto. Microb.Ped.Radio.Sal.Pú.$$cÁrea Microbiología
000153225 773__ $$g(2025), [18 pp.]$$pMicrobiol. spectr.$$tMicrobiology Spectrum$$x2165-0497
000153225 8564_ $$s2299612$$uhttps://zaguan.unizar.es/record/153225/files/texto_completo.pdf$$yVersión publicada
000153225 8564_ $$s2423679$$uhttps://zaguan.unizar.es/record/153225/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000153225 909CO $$ooai:zaguan.unizar.es:153225$$particulos$$pdriver
000153225 951__ $$a2025-10-17-14:35:44
000153225 980__ $$aARTICLE