{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T23:46:38Z","timestamp":1773013598543,"version":"3.50.1"},"reference-count":52,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,9,19]],"date-time":"2019-09-19T00:00:00Z","timestamp":1568851200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,9,19]],"date-time":"2019-09-19T00:00:00Z","timestamp":1568851200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p><jats:italic>Shigella<\/jats:italic> spp., the bacteria responsible for shigellosis, are one of the leading causes of diarrheal morbidity and mortality amongst children. There is a pressing need for the development of novel therapeutics, as resistance of <jats:italic>Shigella<\/jats:italic> to many currently used antibiotics is rapidly emerging. This paper describes the development of robust <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> tools to study antibiotic efficacy against <jats:italic>Shigella flexneri<\/jats:italic>. A novel bioluminescent <jats:italic>S. flexneri<\/jats:italic> strain (<jats:italic>S. flexneri<\/jats:italic> lux1) was generated, which can be used in a mammalian epithelial cell co-culture assay to evaluate antibiotic intracellular and extracellular efficacy. In addition, the <jats:italic>S. flexneri<\/jats:italic> lux1 strain was used with an intraperitoneal (IP) murine model of shigellosis to test the efficacy of ciprofloxacin and ampicillin. Both antibiotics significantly reduced the observed radiance from the gastrointestinal tissue of infected mice compared to vehicle control. Furthermore, plated gastrointestinal tissue homogenate confirmed antibiotic treatment significantly reduced the <jats:italic>S. flexneri<\/jats:italic> infection. However, in contrast to the results generated with tissue homogenate, the radiance data was not able to distinguish between the efficacy of ampicillin and ciprofloxacin. Compared to traditional methods, these models can be utilized for efficient screening of novel antibiotics aiding in the discovery of new treatments against shigellosis.<\/jats:p>","DOI":"10.1038\/s41598-019-49729-2","type":"journal-article","created":{"date-parts":[[2019,9,19]],"date-time":"2019-09-19T10:04:13Z","timestamp":1568887453000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Evaluation of in vitro and in vivo antibiotic efficacy against a novel bioluminescent Shigella flexneri"],"prefix":"10.1038","volume":"9","author":[{"given":"Molly C.","family":"McCloskey","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shareef","family":"Shaheen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lesley","family":"Rabago","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew A.","family":"Hulverson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryan","family":"Choi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lynn K.","family":"Barrett","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samuel L. M.","family":"Arnold","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2019,9,19]]},"reference":[{"key":"49729_CR1","doi-asserted-by":"publisher","first-page":"1459","DOI":"10.1016\/S0140-6736(16)31012-1","volume":"388","author":"GBD Mortality","year":"2016","unstructured":"Mortality, G. B. D. & Causes of Death, C. Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980\u20132015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet 388, 1459\u20131544, https:\/\/doi.org\/10.1016\/S0140-6736(16)31012-1 (2016).","journal-title":"Lancet"},{"key":"49729_CR2","doi-asserted-by":"publisher","first-page":"1291","DOI":"10.1016\/S0140-6736(16)31529-X","volume":"388","author":"J Liu","year":"2016","unstructured":"Liu, J. et al. Use of quantitative molecular diagnostic methods to identify causes of diarrhoea in children: a reanalysis of the GEMS case-control study. Lancet 388, 1291\u20131301, https:\/\/doi.org\/10.1016\/S0140-6736(16)31529-X (2016).","journal-title":"Lancet"},{"key":"49729_CR3","doi-asserted-by":"publisher","first-page":"e564","DOI":"10.1016\/S2214-109X(15)00151-5","volume":"3","author":"JA Platts-Mills","year":"2015","unstructured":"Platts-Mills, J. A. et al. Pathogen-specific burdens of community diarrhoea in developing countries: a multisite birth cohort study (MAL-ED). Lancet Glob Health 3, e564\u2013575, https:\/\/doi.org\/10.1016\/S2214-109X(15)00151-5 (2015).","journal-title":"Lancet Glob Health"},{"key":"49729_CR4","first-page":"133","volume":"43","author":"SK Niyogi","year":"2005","unstructured":"Niyogi, S. K. Shigellosis. J Microbiol 43, 133\u2013143 (2005).","journal-title":"J Microbiol"},{"key":"49729_CR5","first-page":"25","volume":"209","author":"C Parsot","year":"1996","unstructured":"Parsot, C. & Sansonetti, P. J. Invasion and the pathogenesis of Shigella infections. Curr Top Microbiol Immunol 209, 25\u201342 (1996).","journal-title":"Curr Top Microbiol Immunol"},{"key":"49729_CR6","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1007\/s40475-014-0019-6","volume":"1","author":"MB Zaidi","year":"2014","unstructured":"Zaidi, M. B. & Estrada-Garcia, T. Shigella: A Highly Virulent and Elusive Pathogen. Curr Trop Med Rep 1, 81\u201387, https:\/\/doi.org\/10.1007\/s40475-014-0019-6 (2014).","journal-title":"Curr Trop Med Rep"},{"key":"49729_CR7","doi-asserted-by":"publisher","first-page":"1056","DOI":"10.1038\/ng.2369","volume":"44","author":"KE Holt","year":"2012","unstructured":"Holt, K. E. et al. Shigella sonnei genome sequencing and phylogenetic analysis indicate recent global dissemination from Europe. Nat Genet 44, 1056\u20131059, https:\/\/doi.org\/10.1038\/ng.2369 (2012).","journal-title":"Nat Genet"},{"key":"49729_CR8","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2164-15-355","volume":"15","author":"L Rohmer","year":"2014","unstructured":"Rohmer, L. et al. Genomic analysis of the emergence of 20th century epidemic dysentery. BMC Genomics 15, 355, https:\/\/doi.org\/10.1186\/1471-2164-15-355 (2014).","journal-title":"BMC Genomics"},{"key":"49729_CR9","doi-asserted-by":"publisher","first-page":"565","DOI":"10.4103\/0971-5916.187104","volume":"143","author":"N Taneja","year":"2016","unstructured":"Taneja, N. & Mewara, A. Shigellosis: Epidemiology in India. Indian J Med Res 143, 565\u2013576, https:\/\/doi.org\/10.4103\/0971-5916.187104 (2016).","journal-title":"Indian J Med Res"},{"key":"49729_CR10","doi-asserted-by":"publisher","first-page":"e353","DOI":"10.1371\/journal.pmed.0030353","volume":"3","author":"L von Seidlein","year":"2006","unstructured":"von Seidlein, L. et al. A multicentre study of Shigella diarrhoea in six Asian countries: disease burden, clinical manifestations, and microbiology. PLoS Med 3, e353, https:\/\/doi.org\/10.1371\/journal.pmed.0030353 (2006).","journal-title":"PLoS Med"},{"key":"49729_CR11","doi-asserted-by":"publisher","first-page":"e1002055","DOI":"10.1371\/journal.pmed.1002055","volume":"13","author":"H Chung The","year":"2016","unstructured":"Chung The, H. et al. South Asia as a Reservoir for the Global Spread of Ciprofloxacin-Resistant Shigella sonnei: A Cross-Sectional Study. PLoS Med 13, e1002055, https:\/\/doi.org\/10.1371\/journal.pmed.1002055 (2016).","journal-title":"PLoS Med"},{"key":"49729_CR12","doi-asserted-by":"publisher","first-page":"318","DOI":"10.15585\/mmwr.mm6444a3","volume":"64","author":"A Bowen","year":"2015","unstructured":"Bowen, A. et al. Importation and domestic transmission of Shigella sonnei resistant to ciprofloxacin - United States, May 2014-February 2015. MMWR Morb Mortal Wkly Rep 64, 318\u2013320 (2015).","journal-title":"MMWR Morb Mortal Wkly Rep"},{"key":"49729_CR13","unstructured":"WHO. The selection and use of essential medicines, http:\/\/www.who.int\/medicines\/publications\/essentialmedicines\/en\/."},{"key":"49729_CR14","doi-asserted-by":"publisher","first-page":"3181","DOI":"10.1093\/jac\/dkx268","volume":"72","author":"JD Brown","year":"2017","unstructured":"Brown, J. D. et al. Shigella species epidemiology and antimicrobial susceptibility: the implications of emerging azithromycin resistance for guiding treatment, guidelines and breakpoints. J Antimicrob Chemother 72, 3181\u20133186, https:\/\/doi.org\/10.1093\/jac\/dkx268 (2017).","journal-title":"J Antimicrob Chemother"},{"key":"49729_CR15","doi-asserted-by":"publisher","first-page":"345","DOI":"10.3201\/eid2302.161260","volume":"23","author":"YS Liao","year":"2016","unstructured":"Liao, Y. S., Liu, Y. Y., Lo, Y. C. & Chiou, C. S. Azithromycin-Nonsusceptible Shigella flexneri 3a in Men Who Have Sex with Men, Taiwan, 2015\u20132016. Emerg Infect Dis 23, 345\u2013346, https:\/\/doi.org\/10.3201\/eid2302.161260 (2016).","journal-title":"Emerg Infect Dis"},{"key":"49729_CR16","doi-asserted-by":"publisher","first-page":"913","DOI":"10.1016\/S1473-3099(15)00002-X","volume":"15","author":"KS Baker","year":"2015","unstructured":"Baker, K. S. et al. Intercontinental dissemination of azithromycin-resistant shigellosis through sexual transmission: a cross-sectional study. Lancet Infect Dis 15, 913\u2013921, https:\/\/doi.org\/10.1016\/S1473-3099(15)00002-X (2015).","journal-title":"Lancet Infect Dis"},{"key":"49729_CR17","doi-asserted-by":"publisher","first-page":"1503","DOI":"10.1128\/JB.88.5.1503-1518.1964","volume":"88","author":"EH Labrec","year":"1964","unstructured":"Labrec, E. H., Schneider, H. & Magnani, T. J. & Formal, S. B. Epithelial Cell Penetration as an Essential Step in the Pathogenesis of Bacillary Dysentery. J Bacteriol 88, 1503\u20131518 (1964).","journal-title":"J Bacteriol"},{"key":"49729_CR18","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1093\/infdis\/jit399","volume":"209","author":"JY Yang","year":"2014","unstructured":"Yang, J. Y. et al. A mouse model of shigellosis by intraperitoneal infection. J Infect Dis 209, 203\u2013215, https:\/\/doi.org\/10.1093\/infdis\/jit399 (2014).","journal-title":"J Infect Dis"},{"key":"49729_CR19","doi-asserted-by":"publisher","first-page":"222","DOI":"10.2310\/7290.2008.00024","volume":"7","author":"KN Flentie","year":"2008","unstructured":"Flentie, K. N. et al. Stably integrated luxCDABE for assessment of Salmonella invasion kinetics. Mol Imaging 7, 222\u2013233 (2008).","journal-title":"Mol Imaging"},{"key":"49729_CR20","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1186\/1471-2180-10-197","volume":"10","author":"K Howe","year":"2010","unstructured":"Howe, K. et al. Development of stable reporter system cloning luxCDABE genes into chromosome of Salmonella enterica serotypes using Tn7 transposon. BMC Microbiol 10, 197, https:\/\/doi.org\/10.1186\/1471-2180-10-197 (2010).","journal-title":"BMC Microbiol"},{"key":"49729_CR21","doi-asserted-by":"publisher","first-page":"34","DOI":"10.4161\/gmic.2.1.14882","volume":"2","author":"KJ Rhee","year":"2011","unstructured":"Rhee, K. J. et al. Determination of spatial and temporal colonization of enteropathogenic E. coli and enterohemorrhagic E. coli in mice using bioluminescent in vivo imaging. Gut Microbes 2, 34\u201341, https:\/\/doi.org\/10.4161\/gmic.2.1.14882 (2011).","journal-title":"Gut Microbes"},{"key":"49729_CR22","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1093\/jpids\/pix024","volume":"6","author":"GA Levine","year":"2017","unstructured":"Levine, G. A., Walson, J. L., Atlas, H. E., Lamberti, L. M. & Pavlinac, P. B. Defining Pediatric Diarrhea in Low-Resource Settings. J Pediatric Infect Dis Soc 6, 289\u2013293, https:\/\/doi.org\/10.1093\/jpids\/pix024 (2017).","journal-title":"J Pediatric Infect Dis Soc"},{"key":"49729_CR23","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/j.micinf.2016.09.002","volume":"19","author":"D Sharma","year":"2017","unstructured":"Sharma, D. et al. Shigellosis murine model established by intraperitoneal and intranasal route of administration: a comparative comprehension overview. Microbes Infect 19, 47\u201354, https:\/\/doi.org\/10.1016\/j.micinf.2016.09.002 (2017).","journal-title":"Microbes Infect"},{"key":"49729_CR24","doi-asserted-by":"publisher","first-page":"1073","DOI":"10.1128\/AAC.37.5.1073","volume":"37","author":"A Forrest","year":"1993","unstructured":"Forrest, A. et al. Pharmacodynamics of intravenous ciprofloxacin in seriously ill patients. Antimicrob Agents Chemother 37, 1073\u20131081 (1993).","journal-title":"Antimicrob Agents Chemother"},{"key":"49729_CR25","doi-asserted-by":"publisher","first-page":"1725","DOI":"10.1093\/jac\/dkq211","volume":"65","author":"SA Zelenitsky","year":"2010","unstructured":"Zelenitsky, S. A. & Ariano, R. E. Support for higher ciprofloxacin AUC 24\/MIC targets in treating Enterobacteriaceae bloodstream infection. J Antimicrob Chemother 65, 1725\u20131732, https:\/\/doi.org\/10.1093\/jac\/dkq211 (2010).","journal-title":"J Antimicrob Chemother"},{"key":"49729_CR26","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1179\/joc.2001.13.5.563","volume":"13","author":"XG Liu","year":"2001","unstructured":"Liu, X. G. & Li, R. C. Effects of repeated rifabutin administration on the pharmacokinetics of intravenous and oral ciprofloxacin in mice. J Chemother 13, 563\u2013568, https:\/\/doi.org\/10.1179\/joc.2001.13.5.563 (2001).","journal-title":"J Chemother"},{"key":"49729_CR27","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1038\/nbt943","volume":"22","author":"VV Verkhusha","year":"2004","unstructured":"Verkhusha, V. V. & Lukyanov, K. A. The molecular properties and applications of Anthozoa fluorescent proteins and chromoproteins. Nat Biotechnol 22, 289\u2013296, https:\/\/doi.org\/10.1038\/nbt943 (2004).","journal-title":"Nat Biotechnol"},{"key":"49729_CR28","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1146\/annurev.biochem.67.1.509","volume":"67","author":"RY Tsien","year":"1998","unstructured":"Tsien, R. Y. The green fluorescent protein. Annu Rev Biochem 67, 509\u2013544, https:\/\/doi.org\/10.1146\/annurev.biochem.67.1.509 (1998).","journal-title":"Annu Rev Biochem"},{"key":"49729_CR29","doi-asserted-by":"publisher","first-page":"905","DOI":"10.1038\/nmeth819","volume":"2","author":"NC Shaner","year":"2005","unstructured":"Shaner, N. C., Steinbach, P. A. & Tsien, R. Y. A guide to choosing fluorescent proteins. Nat Methods 2, 905\u2013909, https:\/\/doi.org\/10.1038\/nmeth819 (2005).","journal-title":"Nat Methods"},{"key":"49729_CR30","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1162\/153535004773861688","volume":"3","author":"T Troy","year":"2004","unstructured":"Troy, T., Jekic-McMullen, D., Sambucetti, L. & Rice, B. Quantitative comparison of the sensitivity of detection of fluorescent and bioluminescent reporters in animal models. Mol Imaging 3, 9\u201323, https:\/\/doi.org\/10.1162\/153535004773861688 (2004).","journal-title":"Mol Imaging"},{"key":"49729_CR31","doi-asserted-by":"publisher","first-page":"2240","DOI":"10.1128\/AEM.64.6.2240-2246.1998","volume":"64","author":"JB Andersen","year":"1998","unstructured":"Andersen, J. B. et al. New unstable variants of green fluorescent protein for studies of transient gene expression in bacteria. Appl Environ Microbiol 64, 2240\u20132246 (1998).","journal-title":"Appl Environ Microbiol"},{"key":"49729_CR32","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1007\/s11693-006-9001-5","volume":"1","author":"MS Allen","year":"2007","unstructured":"Allen, M. S., Wilgus, J. R., Chewning, C. S., Sayler, G. S. & Simpson, M. L. A destabilized bacterial luciferase for dynamic gene expression studies. Syst Synth Biol 1, 3\u20139, https:\/\/doi.org\/10.1007\/s11693-006-9001-5 (2007).","journal-title":"Syst Synth Biol"},{"key":"49729_CR33","doi-asserted-by":"publisher","first-page":"320","DOI":"10.1093\/tropej\/40.6.320","volume":"40","author":"MR Islam","year":"1994","unstructured":"Islam, M. R., Alam, A. N., Hossain, M. S., Mahalanabis, D. & Hye, H. K. Double-blind comparison of oral gentamicin and nalidixic acid in the treatment of acute shigellosis in children. J Trop Pediatr 40, 320\u2013325 (1994).","journal-title":"J Trop Pediatr"},{"key":"49729_CR34","doi-asserted-by":"publisher","first-page":"743","DOI":"10.1128\/AAC.16.6.743","volume":"16","author":"P Vaudaux","year":"1979","unstructured":"Vaudaux, P. & Waldvogel, F. A. Gentamicin antibacterial activity in the presence of human polymorphonuclear leukocytes. Antimicrob Agents Chemother 16, 743\u2013749 (1979).","journal-title":"Antimicrob Agents Chemother"},{"key":"49729_CR35","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1016\/0076-6879(94)36030-8","volume":"236","author":"EA Elsinghorst","year":"1994","unstructured":"Elsinghorst, E. A. Measurement of invasion by gentamicin resistance. Methods Enzymol 236, 405\u2013420 (1994).","journal-title":"Methods Enzymol"},{"key":"49729_CR36","doi-asserted-by":"publisher","first-page":"505","DOI":"10.3389\/fcimb.2017.00505","volume":"7","author":"TT VanCleave","year":"2017","unstructured":"VanCleave, T. T., Pulsifer, A. R., Connor, M. G., Warawa, J. M. & Lawrenz, M. B. Impact of Gentamicin Concentration and Exposure Time on Intracellular Yersinia pestis. Front Cell Infect Microbiol 7, 505, https:\/\/doi.org\/10.3389\/fcimb.2017.00505 (2017).","journal-title":"Front Cell Infect Microbiol"},{"key":"49729_CR37","doi-asserted-by":"publisher","first-page":"2222","DOI":"10.1128\/IAI.62.6.2222-2228.1994","volume":"62","author":"DA Drevets","year":"1994","unstructured":"Drevets, D. A., Canono, B. P., Leenen, P. J. & Campbell, P. A. Gentamicin kills intracellular Listeria monocytogenes. Infect Immun 62, 2222\u20132228 (1994).","journal-title":"Infect Immun"},{"key":"49729_CR38","doi-asserted-by":"publisher","first-page":"1016","DOI":"10.1128\/IAI.71.2.1016-1019.2003","volume":"71","author":"TS Hamrick","year":"2003","unstructured":"Hamrick, T. S., Diaz, A. H., Havell, E. A., Horton, J. R. & Orndorff, P. E. Influence of extracellular bactericidal agents on bacteria within macrophages. Infect Immun 71, 1016\u20131019 (2003).","journal-title":"Infect Immun"},{"key":"49729_CR39","doi-asserted-by":"publisher","first-page":"514","DOI":"10.1111\/cmi.12527","volume":"18","author":"RS Flannagan","year":"2016","unstructured":"Flannagan, R. S., Heit, B. & Heinrichs, D. E. Intracellular replication of Staphylococcus aureus in mature phagolysosomes in macrophages precedes host cell death, and bacterial escape and dissemination. Cell Microbiol 18, 514\u2013535, https:\/\/doi.org\/10.1111\/cmi.12527 (2016).","journal-title":"Cell Microbiol"},{"key":"49729_CR40","doi-asserted-by":"publisher","first-page":"920","DOI":"10.1128\/AAC.00382-07","volume":"52","author":"O Menashe","year":"2008","unstructured":"Menashe, O., Kaganskaya, E., Baasov, T. & Yaron, S. Aminoglycosides affect intracellular Salmonella enterica serovars typhimurium and virchow. Antimicrob Agents Chemother 52, 920\u2013926, https:\/\/doi.org\/10.1128\/AAC.00382-07 (2008).","journal-title":"Antimicrob Agents Chemother"},{"key":"49729_CR41","doi-asserted-by":"publisher","first-page":"4826","DOI":"10.1128\/IAI.00454-07","volume":"75","author":"S Paetzold","year":"2007","unstructured":"Paetzold, S., Lourido, S., Raupach, B. & Zychlinsky, A. Shigella flexneri phagosomal escape is independent of invasion. Infect Immun 75, 4826\u20134830, https:\/\/doi.org\/10.1128\/IAI.00454-07 (2007).","journal-title":"Infect Immun"},{"key":"49729_CR42","doi-asserted-by":"publisher","first-page":"1089","DOI":"10.1016\/0300-9084(88)90271-4","volume":"70","author":"BB Finlay","year":"1988","unstructured":"Finlay, B. B. & Falkow, S. Comparison of the invasion strategies used by Salmonella cholerae-suis, Shigella flexneri and Yersinia enterocolitica to enter cultured animal cells: endosome acidification is not required for bacterial invasion or intracellular replication. Biochimie 70, 1089\u20131099 (1988).","journal-title":"Biochimie"},{"key":"49729_CR43","doi-asserted-by":"publisher","first-page":"e9572","DOI":"10.1371\/journal.pone.0009572","volume":"5","author":"K Galmbacher","year":"2010","unstructured":"Galmbacher, K. et al. Shigella mediated depletion of macrophages in a murine breast cancer model is associated with tumor regression. PLoS One 5, e9572, https:\/\/doi.org\/10.1371\/journal.pone.0009572 (2010).","journal-title":"PLoS One"},{"key":"49729_CR44","doi-asserted-by":"publisher","unstructured":"Lapaquette, P. et al. Shigella entry unveils a calcium\/calpain-dependent mechanism for inhibiting sumoylation. Elife 6, https:\/\/doi.org\/10.7554\/eLife.27444 (2017).","DOI":"10.7554\/eLife.27444"},{"key":"49729_CR45","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1111\/j.1472-8206.2008.00572.x","volume":"22","author":"G Lafforgue","year":"2008","unstructured":"Lafforgue, G. et al. Oral absorption of ampicillin: role of paracellular route vs. PepT1 transporter. Fundam Clin Pharmacol 22, 189\u2013201, https:\/\/doi.org\/10.1111\/j.1472-8206.2008.00572.x (2008).","journal-title":"Fundam Clin Pharmacol"},{"issue":"5","key":"49729_CR46","doi-asserted-by":"publisher","first-page":"615","DOI":"10.1080\/19490976.2018.1564430","volume":"10","author":"Pedro Henrique Q.S. Medeiros","year":"2019","unstructured":"PH, Q. S. M. et al. A murine model of diarrhea, growth impairment and metabolic disturbances with Shigella flexneri infection and the role of zinc deficiency. Gut Microbes, 1\u201316, https:\/\/doi.org\/10.1080\/19490976.2018.1564430 (2019).","journal-title":"Gut Microbes"},{"key":"49729_CR47","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1046\/j.1462-5822.2003.00295.x","volume":"5","author":"MI Fernandez","year":"2003","unstructured":"Fernandez, M. I. et al. A newborn mouse model for the study of intestinal pathogenesis of shigellosis. Cell Microbiol 5, 481\u2013491 (2003).","journal-title":"Cell Microbiol"},{"key":"49729_CR48","doi-asserted-by":"publisher","first-page":"4924","DOI":"10.4049\/jimmunol.180.7.4924","volume":"180","author":"MI Fernandez","year":"2008","unstructured":"Fernandez, M. I. et al. Maturation of paneth cells induces the refractory state of newborn mice to Shigella infection. J Immunol 180, 4924\u20134930 (2008).","journal-title":"J Immunol"},{"key":"49729_CR49","doi-asserted-by":"publisher","first-page":"1342","DOI":"10.1128\/IAI.66.4.1342-1348.1998","volume":"66","author":"SS Way","year":"1998","unstructured":"Way, S. S., Borczuk, A. C., Dominitz, R. & Goldberg, M. B. An essential role for gamma interferon in innate resistance to Shigella flexneri infection. Infect Immun 66, 1342\u20131348 (1998).","journal-title":"Infect Immun"},{"key":"49729_CR50","doi-asserted-by":"publisher","first-page":"711","DOI":"10.1093\/infdis\/162.3.711","volume":"162","author":"ML Bennish","year":"1990","unstructured":"Bennish, M. L., Salam, M. A., Haider, R. & Barza, M. Therapy for shigellosis. II. Randomized, double-blind comparison of ciprofloxacin and ampicillin. J Infect Dis 162, 711\u2013716 (1990).","journal-title":"J Infect Dis"},{"key":"49729_CR51","doi-asserted-by":"publisher","first-page":"3642","DOI":"10.1128\/IAI.63.9.3642-3648.1995","volume":"63","author":"LM Pope","year":"1995","unstructured":"Pope, L. M., Reed, K. E. & Payne, S. M. Increased protein secretion and adherence to HeLa cells by Shigella spp. following growth in the presence of bile salts. Infect Immun 63, 3642\u20133648 (1995).","journal-title":"Infect Immun"},{"key":"49729_CR52","doi-asserted-by":"publisher","first-page":"1749","DOI":"10.1086\/647952","volume":"49","author":"JH Jorgensen","year":"2009","unstructured":"Jorgensen, J. H. & Ferraro, M. J. Antimicrobial susceptibility testing: a review of general principles and contemporary practices. Clin Infect Dis 49, 1749\u20131755, https:\/\/doi.org\/10.1086\/647952 (2009).","journal-title":"Clin Infect Dis"}],"updated-by":[{"DOI":"10.1038\/s41598-020-59766-x","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2020,2,11]],"date-time":"2020-02-11T00:00:00Z","timestamp":1581379200000}}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-49729-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-49729-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-49729-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T13:45:17Z","timestamp":1671284717000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-49729-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,9,19]]},"references-count":52,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["49729"],"URL":"https:\/\/doi.org\/10.1038\/s41598-019-49729-2","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,9,19]]},"assertion":[{"value":"26 June 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 August 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 September 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 February 2020","order":4,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Correction","order":5,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"An amendment to this paper has been published and can be accessed via a link at the top of the paper.","order":6,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"13567"}}