{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T14:57:54Z","timestamp":1777474674702,"version":"3.51.4"},"reference-count":56,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,1,6]],"date-time":"2023-01-06T00:00:00Z","timestamp":1672963200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia (FCT)","award":["PTDC\/SAU-INF\/28182\/2017"],"award-info":[{"award-number":["PTDC\/SAU-INF\/28182\/2017"]}]},{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia (FCT)","award":["EXPL\/SAU-INF\/0742\/2021"],"award-info":[{"award-number":["EXPL\/SAU-INF\/0742\/2021"]}]},{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia (FCT)","award":["UIDB\/04138\/2020"],"award-info":[{"award-number":["UIDB\/04138\/2020"]}]},{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia (FCT)","award":["2021.07978.BD"],"award-info":[{"award-number":["2021.07978.BD"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Mycobacterium tuberculosis is able to establish a chronic colonization of lung macrophages in a controlled replication manner, giving rise to a so-called latent infection. Conversely, when intracellular bacteria undergo actively uncontrolled replication rates, they provide the switch for the active infection called tuberculosis to occur. Our group found that the pathogen is able to manipulate the activity of endolysosomal enzymes, cathepsins, directly at the level of gene expression or indirectly by regulating their natural inhibitors, cystatins. To provide evidence for the crucial role of cathepsin manipulation for the success of tuberculosis bacilli in their intracellular survival, we used liposomal delivery of saquinavir. This protease inhibitor was previously found to be able to increase cathepsin proteolytic activity, overcoming the pathogen induced blockade. In this study, we demonstrate that incorporation in liposomes was able to increase the efficiency of saquinavir internalization in macrophages, reducing cytotoxicity at higher concentrations. Consequently, our results show a significant impact on the intracellular killing not only to reference and clinical strains susceptible to current antibiotic therapy but also to multidrug- and extensively drug-resistant (XDR) Mtb strains. Altogether, this indicates the manipulation of cathepsins as a fine-tuning strategy used by the pathogen to survive and replicate in host cells.<\/jats:p>","DOI":"10.3390\/ijms24021142","type":"journal-article","created":{"date-parts":[[2023,1,9]],"date-time":"2023-01-09T01:36:17Z","timestamp":1673228177000},"page":"1142","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Liposomal Delivery of Saquinavir to Macrophages Overcomes Cathepsin Blockade by Mycobacterium tuberculosis and Helps Control the Phagosomal Replicative Niches"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9602-1516","authenticated-orcid":false,"given":"David","family":"Pires","sequence":"first","affiliation":[{"name":"Host-Pathogen Interactions Unit, Research Institute for Medicines, iMed-ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"},{"name":"Center for Interdisciplinary Research in Health, Cat\u00f3lica Medical School, Universidade Cat\u00f3lica Portuguesa, Estrada Oct\u00e1vio Pato, 2635-631 Rio de Mouro, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3997-9618","authenticated-orcid":false,"given":"Manoj","family":"Mandal","sequence":"additional","affiliation":[{"name":"Host-Pathogen Interactions Unit, Research Institute for Medicines, iMed-ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7725-4701","authenticated-orcid":false,"given":"Jacinta","family":"Pinho","sequence":"additional","affiliation":[{"name":"Advanced Technologies for Drug Delivery, Research Institute for Medicines, iMed-ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3794-457X","authenticated-orcid":false,"given":"Maria Jo\u00e3o","family":"Catal\u00e3o","sequence":"additional","affiliation":[{"name":"Host-Pathogen Interactions Unit, Research Institute for Medicines, iMed-ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7807-4726","authenticated-orcid":false,"given":"Ant\u00f3nio Jos\u00e9","family":"Almeida","sequence":"additional","affiliation":[{"name":"Advanced Technologies for Drug Delivery, Research Institute for Medicines, iMed-ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7434-7208","authenticated-orcid":false,"given":"Jos\u00e9 Miguel","family":"Azevedo-Pereira","sequence":"additional","affiliation":[{"name":"Host-Pathogen Interactions Unit, Research Institute for Medicines, iMed-ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6814-7226","authenticated-orcid":false,"given":"Maria Manuela","family":"Gaspar","sequence":"additional","affiliation":[{"name":"Advanced Technologies for Drug Delivery, Research Institute for Medicines, iMed-ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5934-0198","authenticated-orcid":false,"given":"Elsa","family":"Anes","sequence":"additional","affiliation":[{"name":"Host-Pathogen Interactions Unit, Research Institute for Medicines, iMed-ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Hershberg, R., Lipatov, M., Small, P.M., Sheffer, H., Niemann, S., Homolka, S., Roach, J.C., Kremer, K., Petrov, D.A., and Feldman, M.W. (2008). High Functional Diversity in Mycobacterium tuberculosis Driven by Genetic Drift and Human Demography. 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