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The emergence of antibiotic\u2010resistant strains has consistently challenged the successful treatment of typhoid fever with conventional antibiotics. Antimicrobial resistance (AMR) in <jats:italic>Salmonella<\/jats:italic> is acquired either by mutations in the genomic DNA or by acquiring extrachromosomal DNA via horizontal gene transfer. In addition, <jats:italic>Salmonella<\/jats:italic> can form a subpopulation of antibiotic persistent (AP) cells that can survive at high concentrations of antibiotics. These have reduced the effectiveness of the first and second lines of antibiotics used to treat <jats:italic>Salmonella<\/jats:italic> infection. The recurrent and chronic carriage of <jats:italic>S.<\/jats:italic> Typhi in human hosts further complicates the treatment process, as a remarkable shift in the immune response from pro\u2010inflammatory Th1 to anti\u2010inflammatory Th2 is observed. Recent studies have also highlighted the overlap between AP, persistent infection (PI) and AMR. These incidents have revealed several areas of research. In this review, we have put forward a timeline for the evolution of antibiotic resistance in <jats:italic>Salmonella<\/jats:italic> and discussed the different mechanisms of the same availed by the pathogen at the genotypic and phenotypic levels. Further, we have presented a detailed discussion on <jats:italic>Salmonella<\/jats:italic> antibiotic persistence (AP), PI, the host and bacterial virulence factors that can influence PI, and how both AP and PI can lead to AMR.<\/jats:p>","DOI":"10.1111\/mmi.15209","type":"journal-article","created":{"date-parts":[[2023,12,10]],"date-time":"2023-12-10T08:31:22Z","timestamp":1702197082000},"page":"213-229","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Defying the odds: Determinants of the antimicrobial response of <i>Salmonella<\/i> Typhi and their interplay"],"prefix":"10.1111","volume":"121","author":[{"given":"Atish Roy","family":"Chowdhury","sequence":"first","affiliation":[{"name":"Department of Microbiology and Cell Biology, Division of Biological Sciences Indian Institute of Science  Bangalore 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