{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T15:04:33Z","timestamp":1778857473459,"version":"3.51.4"},"reference-count":75,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,11,12]],"date-time":"2021-11-12T00:00:00Z","timestamp":1636675200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>One of the main hallmarks of tuberculosis (TB) is the ability of the causative agent to transform into a stage of dormancy and the capability of long persistence in the host phagocytes. It is believed that approximately one-third of the population of the world is latently infected with <jats:italic>Mycobacterium tuberculosis<\/jats:italic> (<jats:italic>Mtb<\/jats:italic>), and 5%\u201310% of these individuals can develop clinical manifestations of active TB even decades after the initial infection. In this latent, intracellular form, the <jats:italic>bacillus<\/jats:italic> is shielded by an extremely robust cell wall and becomes phenotypically resistant to most antituberculars. Therefore, there is a clear rationale to develop novel compounds or carrier-conjugated constructs of existing drugs that are effective against the intracellular form of the bacilli. In this paper, we describe an experimental road map to define optimal candidates against intracellular <jats:italic>Mtb<\/jats:italic> and potential compounds effective in the therapy of latent TB. To validate our approach, isoniazid, a first-line antitubercular drug was employed, which is active against extracellular <jats:italic>Mtb<\/jats:italic> in the submicromolar range, but ineffective against the intracellular form of the bacteria. Cationic peptide conjugates of isoniazid were synthesized and employed to study the host-directed drug delivery. To measure the intracellular killing activity of the compounds, <jats:italic>Mtb<\/jats:italic>-infected MonoMac-6 human monocytic cells were utilized. We have assessed the antitubercular activity, cytotoxicity, membrane interactions in combination with internalization efficacy, localization, and penetration ability on interface and tissue-mimicking 3D models. Based on these <jats:italic>in vitro<\/jats:italic> data, most active compounds were further evaluated <jats:italic>in vivo<\/jats:italic> in a murine model of TB. Intraperitoneal infectious route was employed to induce a course of slowly progressive and systemic disease. The well-being of the animals, monitored by the body weight, allows a prolonged experimental setup and provides a great opportunity to test the long-term activity of the drug candidates. Having shown the great potency of this simple and suitable experimental design for antimicrobial research, the proposed novel assay platform could be used in the future to develop further innovative and highly effective antituberculars.<\/jats:p>","DOI":"10.3389\/fimmu.2021.750496","type":"journal-article","created":{"date-parts":[[2021,11,12]],"date-time":"2021-11-12T04:43:08Z","timestamp":1636692188000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":20,"title":["Novel Assay Platform to Evaluate Intracellular Killing of Mycobacterium tuberculosis: In Vitro and In Vivo Validation"],"prefix":"10.3389","volume":"12","author":[{"given":"Kata","family":"Horv\u00e1ti","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kinga","family":"Fodor","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bernadett","family":"P\u00e1lyi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Judit","family":"Henczk\u00f3","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gyula","family":"Balka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gerg\u0151","family":"Gyulai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"\u00c9va","family":"Kiss","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Be\u00e1ta","family":"Biri-Kov\u00e1cs","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zsuzsanna","family":"Senoner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Szilvia","family":"B\u0151sze","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,11,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-2600(19)30421-7","article-title":"WHO Global Progress Report on Tuberculosis Elimination (Vol 8, Pg 19, 2020)","volume":"8","author":"Harding","year":"2020","journal-title":"Lancet Respir Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijid.2021.02.107","article-title":"Global Tuberculosis Report 2020 - Reflections on the Global TB Burden, Treatment and Prevention Efforts","author":"Chakaya","year":"2021","journal-title":"Int J Infect Dis"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro2236","article-title":"The Spectrum of Latent Tuberculosis: Rethinking the Biology and Intervention Strategies","volume":"7","author":"Barry","year":"2009","journal-title":"Nat Rev Microbiol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1097\/QCO.0000000000000367","article-title":"New Concepts in Understanding Latent Tuberculosis","volume":"30","author":"Dodd","year":"2017","journal-title":"Curr Opin Infect Dis"},{"key":"B5","doi-asserted-by":"publisher","first-page":"342","DOI":"10.1186\/1756-0500-6-342","article-title":"Understanding of Latent Tuberculosis, Its Treatment and Treatment Side Effects in Immigrant and Refugee Patients","volume":"6","author":"Butcher","year":"2013","journal-title":"BMC Res Notes"},{"key":"B6","doi-asserted-by":"publisher","first-page":"e1006421","DOI":"10.1371\/journal.ppat.1006421","article-title":"Experimental Study of Tuberculosis: From Animal Models to Complex Cell Systems and Organoids","volume":"13","author":"Fonseca","year":"2017","journal-title":"PloS Pathog"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1128\/microbiolspec.TBTB2-0002-2015","article-title":"Mouse and Guinea Pig Models of Tuberculosis","volume":"4","author":"Orme","year":"2016","journal-title":"Microbiol Spectr"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.tube.2004.08.001","article-title":"Mouse and Guinea Pig Models for Testing New Tuberculosis Vaccines","volume":"85","author":"Orme","year":"2005","journal-title":"Tuberculosis"},{"key":"B9","doi-asserted-by":"publisher","first-page":"a018564","DOI":"10.1101\/cshperspect.a018564","article-title":"Modeling Tuberculosis in Nonhuman Primates","volume":"4","author":"Scanga","year":"2014","journal-title":"Cold Spring Harb Perspect Med"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2012.07.019","article-title":"Spontaneous Latency in a Rabbit Model of Pulmonary Tuberculosis","volume":"181","author":"Subbian","year":"2012","journal-title":"Am J Pathol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.tube.2008.08.004","article-title":"Tuberculosis Genes Expressed During Persistence and Reactivation in the Resistant Rabbit Model","volume":"89","author":"Kesavan","year":"2009","journal-title":"Tuberculosis"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1080\/1040841X.2018.1523132","article-title":"The Zebrafish Model of Tuberculosis - No Lungs Needed","volume":"44","author":"Bouz","year":"2018","journal-title":"Crit Rev Microbiol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.016089","article-title":"Fit for Consumption: Zebrafish as a Model for Tuberculosis","volume":"7","author":"Cronan","year":"2014","journal-title":"Dis Models Mech"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2012.10.002","article-title":"Insights Into Tuberculosis From the Zebrafish Model","volume":"18","author":"Berg","year":"2012","journal-title":"Trends Mol Med"},{"key":"B15","doi-asserted-by":"publisher","first-page":"e0158849","DOI":"10.1371\/journal.pone.0158849","article-title":"A Mouse Model of Latent Tuberculosis Infection to Study Intervention Strategies to Prevent Reactivation","volume":"11","author":"Kupz","year":"2016","journal-title":"PloS One"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-3083.1999.00596.x","article-title":"A Mouse Model for Slowly Progressive Primary Tuberculosis","volume":"50","author":"Mustafa","year":"1999","journal-title":"Scandinavian J Immunol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1378\/chest.09-0903","article-title":"Neutrophils Are the Predominant Infected Phagocytic Cells in the Airways of Patients With Active Pulmonary TB","volume":"137","author":"Eum","year":"2010","journal-title":"Chest"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1111\/j.1462-5822.2005.00506.x","article-title":"How C-Type Lectins Detect Pathogens","volume":"7","author":"Cambi","year":"2005","journal-title":"Cell Microbiol"},{"key":"B19","article-title":"The Siglec-1\/CD169 Macrophage Receptor: A Catalyst for the Infectious Synergy Between Mycobacterium Tuberculosis and HIV-1","volume":"36","author":"Dupont","year":"2020","journal-title":"M S-Med Sci"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.66.4.1277-1281.1998","article-title":"Macrophage Receptors for Mycobacterium Tuberculosis","volume":"66","author":"Ernst","year":"1998","journal-title":"Infection Immun"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1007\/s00430-016-0470-1","article-title":"C-Type Lectin Receptors in Tuberculosis: What We Know","volume":"205","author":"Goyal","year":"2016","journal-title":"Med Microbiol Immunol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1111\/j.1574-6976.2012.00331.x","article-title":"Mycobacterium Tuberculosis: Success Through Dormancy","volume":"36","author":"Gengenbacher","year":"2012","journal-title":"FEMS Microbiol Rev"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20020340","article-title":"The Immune Escape Mechanisms of Mycobacterium Tuberculosis","volume":"20","author":"Zhai","year":"2019","journal-title":"Int J Mol Sci"},{"key":"B24","doi-asserted-by":"publisher","first-page":"e13337","DOI":"10.1111\/cmi.13337","article-title":"Advances in Host-Based Screening for Compounds With Intracellular Anti-Mycobacterial Activity","volume":"23","author":"Subhash","year":"2021","journal-title":"Cell Microbiol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2013.01.008","article-title":"Integration of Chemical and RNAi Multiparametric Profiles Identifies Triggers of Intracellular Mycobacterial Killing","volume":"13","author":"Sundaramurthy","year":"2013","journal-title":"Cell Host Microbe"},{"key":"B26","doi-asserted-by":"publisher","first-page":"fty017","DOI":"10.1093\/femspd\/fty017","article-title":"Fluorescent Mycobacterium Tuberculosis Reporters: Illuminating Host-Pathogen Interactions","volume":"76","author":"MacGilvary","year":"2018","journal-title":"Pathog Dis"},{"key":"B27","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/j.ijmyco.2013.12.002","article-title":"Coupling Reporter Expression to Respiration Detects Active as Well as Dormant Mycobacteria In Vitro and in Mouse Tissues","volume":"3","author":"Verma","year":"2014","journal-title":"Int J Mycobacteriol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3389\/Fmicb.2020.591866","article-title":"Development and Optimization of Chromosomally-Integrated Fluorescent Mycobacterium Tuberculosis Reporter Constructs","volume":"11","author":"Kolbe","year":"2020","journal-title":"Front Microbiol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"e1003946","DOI":"10.1371\/journal.ppat.1003946","article-title":"Identification of Host-Targeted Small Molecules That Restrict Intracellular Mycobacterium Tuberculosis Growth","volume":"10","author":"Stanley","year":"2014","journal-title":"PloS Pathog"},{"key":"B30","doi-asserted-by":"publisher","first-page":"e1004679","DOI":"10.1371\/journal.ppat.1004679","article-title":"Novel Inhibitors of Cholesterol Degradation in Mycobacterium Tuberculosis Reveal How the Bacterium's Metabolism Is Constrained by the Intracellular Environment","volume":"11","author":"VanderVen","year":"2015","journal-title":"PloS Pathog"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201404137","article-title":"Functional Drug Screening Reveals Anticonvulsants as Enhancers of mTOR-Independent Autophagic Killing of Mycobacterium Tuberculosis Through Inositol Depletion","volume":"7","author":"Schiebler","year":"2015","journal-title":"EMBO Mol Med"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3262","article-title":"Discovery of Q203, a Potent Clinical Candidate for the Treatment of Tuberculosis","volume":"19","author":"Pethe","year":"2013","journal-title":"Nat Med"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3389\/Fmicb.2020.553962","article-title":"High-Content Screening of Eukaryotic Kinase Inhibitors Identify CHK2 Inhibitor Activity Against Mycobacterium Tuberculosis","volume":"11","author":"Shapira","year":"2020","journal-title":"Front Microbiol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01601-19","article-title":"THP-1 and Dictyostelium Infection Models for Screening and Characterization of Anti-Mycobacterium Abscessus Hit Compounds","volume":"64","author":"Richter","year":"2020","journal-title":"Antimicrob Agents Chemother"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1021\/acs.bioconjchem.8b00156","article-title":"Surface Layer Modification of Poly(D,L-Lactic-Co-Glycolic Acid) Nanoparticles With Targeting Peptide: A Convenient Synthetic Route for Pluronic F127-Tuftsin Conjugate","volume":"29","author":"Horvati","year":"2018","journal-title":"Bioconjugate Chem"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.tube.2015.02.026","article-title":"Antimycobacterial Activity of Peptide Conjugate of Pyridopyrimidine Derivative Against Mycobacterium Tuberculosis in a Series of In Vitro and In Vivo Models","volume":"95","author":"Horvati","year":"2015","journal-title":"Tuberculosis"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1089\/adt.2014.573","article-title":"Three-Dimensional Cell Culture Systems and Their Applications in Drug Discovery and Cell-Based Biosensors","volume":"12","author":"Edmondson","year":"2014","journal-title":"Assay Drug Dev Technol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1152\/physiol.00041.2016","article-title":"In Vitro Models to Study Human Lung Development, Disease and Homeostasis","volume":"32","author":"Miller","year":"2017","journal-title":"Physiol (Bethesda)"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1021\/bc500476x","article-title":"Nanoparticle Encapsulated Lipopeptide Conjugate of Antitubercular Drug Isoniazid: In Vitro Intracellular Activity and In Vivo Efficacy in a Guinea Pig Model of Tuberculosis","volume":"25","author":"Horvati","year":"2014","journal-title":"Bioconjugate Chem"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00153-08","article-title":"Intracellular Time Course, Pharmacokinetics, and Biodistribution of Isoniazid and Rifabutin Following Pulmonary Delivery of Inhalable Microparticles to Mice","volume":"52","author":"Verma","year":"2008","journal-title":"Antimicrob Agents Chemother"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1097\/FPC.0000000000000232","article-title":"PharmGKB Summary: Isoniazid Pathway, Pharmacokinetics","volume":"26","author":"Klein","year":"2016","journal-title":"Pharmacogenetics Genomics"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/nature17042","article-title":"Antibacterial Drug Discovery in the Resistance Era","volume":"529","author":"Brown","year":"2016","journal-title":"Nature"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.4155\/fmc.12.76","article-title":"Peptides and Peptide Conjugates: Therapeutics on the Upward Path","volume":"4","author":"Ahrens","year":"2012","journal-title":"Future Med Chem"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1002\/psc.1129","article-title":"Peptide Conjugates of Therapeutically Used Antitubercular Isoniazid - Design, Synthesis and Antimycobacterial Effect","volume":"15","author":"Horvati","year":"2009","journal-title":"J Pept Sci"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.2910410324","article-title":"Establishment of a Human Cell-Line (Mono Mac-6) With Characteristics of Mature Monocytes","volume":"41","author":"Zieglerheitbrock","year":"1988","journal-title":"Int J Cancer"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1038\/aps.2010.214","article-title":"Establishment of Human Continuous Cell Lines From Squamous Cell, Adeno- and Small Cell Carcinoma of the Lung and the Results of Heterotransplantation","volume":"22","author":"Hiraki S","year":"1982","journal-title":"Nihon Haigan Gakkai"},{"key":"B47","doi-asserted-by":"publisher","first-page":"691","DOI":"10.4044\/joma1947.97.7-8_691","article-title":"Experimental Model of Human Lung Cancer, Part I. Establishment and Characterization of New Tissue Culture Cell Lines From Human Squamous Cell Carcinoma and Adenocarcinoma of the Lung","volume":"97","author":"Watanabe","year":"1985","journal-title":"Okayama Igakkai Zasshi"},{"key":"B48","article-title":"Inhibitory Effects of Cholera-Toxin on In-Vitro Growth of Human Lung-Cancer Cell-Lines","volume":"8","author":"Kiura","year":"1993","journal-title":"Anti-Cancer Drug Design"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/59.1.221","article-title":"127 Cultured Human Tumor-Cell Lines Producing Tumors in Nude Mice","volume":"59","author":"Fogh","year":"1977","journal-title":"Jnci-Journal Natl Cancer Institute"},{"key":"B50","article-title":"Distinction of 71 Cultured Human-Tumor Cell-Lines by Polymorphic Enzyme Analysis","volume":"66","author":"Wright","year":"1981","journal-title":"J Natl Cancer Institute"},{"key":"B51","doi-asserted-by":"publisher","first-page":"10A","DOI":"10.1002\/9780471729259.mc10a01s6","article-title":"Laboratory Maintenance of Mycobacterium Tuberculosis","volume":"6","author":"Larsen","year":"2007","journal-title":"Curr Protoc Microbiol"},{"key":"B52","first-page":"589","article-title":"Who Co-Operative Studies on a Simple Culture Technique for the Isolation of Mycobacteria. 1. Preparation, Lyophilization and Reconstitution of a Simple Semi-Synthetic Concentrated Liquid Medium; Culture Technique; Growth Pattern of Different Mycobacteria","volume":"29","author":"Sula","year":"1963","journal-title":"Bull World Health Organ"},{"key":"B53","article-title":"Who Co-Operative Studies on a Simple Culture Technique for the Isolation of Mycobacteria. 2. Comparison of the Efficacy of Lyophilized Liquid Medium With That of Loewenstein-Jensen (L-J) Medium","volume":"29","author":"Sula","year":"1963","journal-title":"Bull World Health Organ"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2006.05.030","article-title":"Synthesis and Antimicrobial Evaluation of New 2-Substituted 5,7-Di-Tert-Butylbenzoxazoles","volume":"14","author":"Vinsova","year":"2006","journal-title":"Bioorg Med Chem"},{"key":"B55","doi-asserted-by":"publisher","first-page":"2982","DOI":"10.1021\/acs.jmedchem.0c01399","article-title":"Cellular Internalization and Inhibition Capacity of New Anti-Glioma Peptide Conjugates: Physicochemical Characterization and Evaluation on Various Monolayer- and 3D-Spheroid-Based In Vitro Platforms","volume":"64","author":"Baranyai","year":"2021","journal-title":"J Med Chem"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1016\/j.meegid.2016.09.004","article-title":"Overview on Mechanisms of Isoniazid Action and Resistance in Mycobacterium Tuberculosis","volume":"45","author":"Unissa","year":"2016","journal-title":"Infect Genet Evol"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2006.05467.x","article-title":"Mechanisms of Action of Isoniazid","volume":"62","author":"Timmins","year":"2006","journal-title":"Mol Microbiol"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3412","article-title":"Sterilization of Granulomas Is Common in Active and Latent Tuberculosis Despite Within-Host Variability in Bacterial Killing","volume":"20","author":"Lin","year":"2014","journal-title":"Nat Med"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.05993-11","article-title":"An Isoniazid Analogue Promotes Mycobacterium Tuberculosis-Nanoparticle Interactions and Enhances Bacterial Killing by Macrophages","volume":"56","author":"de Faria","year":"2012","journal-title":"Antimicrob Agents Chemother"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1038\/358591a0","article-title":"The Catalase Peroxidase Gene and Isoniazid Resistance of Mycobacterium-Tuberculosis","volume":"358","author":"Zhang","year":"1992","journal-title":"Nature"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsb.2015.04.008","article-title":"Crystal Structure of the Enoyl-ACP Reductase of Mycobacterium Tuberculosis (InhA) in the Apo-Form and in Complex With the Active Metabolite of Isoniazid Pre-Formed by a Biomimetic Approach","volume":"190","author":"Chollet","year":"2015","journal-title":"J Struct Biol"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1021\/ja073160k","article-title":"New Insight Into the Mechanism of Action of and Resistance to Isoniazid: Interaction of Mycobacterium Tuberculosis Enoyl-ACP Reductase With INH-NADP","volume":"129","author":"Argyrou","year":"2007","journal-title":"J Am Chem Soc"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinthera.2013.01.003","article-title":"Oral Bioavailability of Rifampicin, Isoniazid, Ethambutol, and Pyrazinamide in a 4-Drug Fixed-Dose Combination Compared With the Separate Formulations in Healthy Chinese Male Volunteers","volume":"35","author":"Xu","year":"2013","journal-title":"Clin Ther"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.50.4.1170-1177.2006","article-title":"Determinants of Rifampin, Isoniazid, Pyrazinamide, and Ethambutol Pharmacokinetics in a Cohort of Tuberculosis Patients","volume":"50","author":"McIlleron","year":"2006","journal-title":"Antimicrob Agents Chemother"},{"key":"B65","doi-asserted-by":"publisher","first-page":"1901522","DOI":"10.1183\/13993003.01522-2019","article-title":"Surveillance of Adverse Events in the Treatment of Drug-Resistant Tuberculosis: First Global Report","volume":"54","author":"Borisov","year":"2019","journal-title":"Eur Respir J"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.3389\/Fcimb.2020.612931","article-title":"Antimicrobial Peptides and Cell-Penetrating Peptides for Treating Intracellular Bacterial Infections","volume":"5","author":"Buccini","year":"2021","journal-title":"Front Cell Infect Microbiol"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejps.2008.04.002","article-title":"Targeting of Efavirenz Loaded Tuftsin Conjugated Poly(Propyleneimine) Dendrimers to HIV Infected Macrophages In Vitro","volume":"34","author":"Dutta","year":"2008","journal-title":"Eur J Pharm Sci"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1983.tb37097.x","article-title":"Receptor-Mediated Internalization of Tuftsin","volume":"419","author":"Amoscato","year":"1983","journal-title":"Ann NY Acad Sci"},{"key":"B69","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1111\/j.1749-6632.1983.tb37095.x","article-title":"Tuftsin Receptors","volume":"419","author":"Gottlieb","year":"1983","journal-title":"Ann Ny Acad Sci"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21062197","article-title":"Drug Conjugation Induced Modulation of Structural and Membrane Interaction Features of Cationic Cell-Permeable Peptides","volume":"21","author":"Pari","year":"2020","journal-title":"Int J Mol Sci"},{"key":"B71","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1002\/chir.22784","article-title":"Hemin and Bile Pigments Are the Secondary Structure Regulators of Intrinsically Disordered Antimicrobial Peptides","volume":"30","author":"Zsila","year":"2018","journal-title":"Chirality"},{"key":"B72","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1016\/j.ijbiomac.2019.01.209","article-title":"Disorder-To-Helix Conformational Conversion of the Human Immunomodulatory Peptide LL-37 Induced by Antiinflammatory Drugs, Food Dyes and Some Metabolites","volume":"129","author":"Zsila","year":"2019","journal-title":"Int J Biol Macromolecules"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1002\/pro.3364","article-title":"Secondary Structure of Cell-Penetrating Peptides During Interaction With Fungal Cells","volume":"27","author":"Gong","year":"2018","journal-title":"Protein Sci"},{"key":"B74","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1016\/S0005-2736(99)00201-1","article-title":"Structural Features of Helical Antimicrobial Peptides: Their Potential to Modulate Activity on Model Membranes and Biological Cells","volume":"1462","author":"Dathe","year":"1999","journal-title":"Biochim Et Biophys Acta-Biomembranes"},{"key":"B75","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1038\/nature01451","article-title":"Regulated Portals of Entry Into the Cell","volume":"422","author":"Conner","year":"2003","journal-title":"Nature"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.750496\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,12]],"date-time":"2021-11-12T04:43:13Z","timestamp":1636692193000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.750496\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,12]]},"references-count":75,"alternative-id":["10.3389\/fimmu.2021.750496"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.750496","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,12]]},"article-number":"750496"}}