| Summary: | Resistance to and survival under acidic conditions are critical for <i>Salmonella</i> to infect the host. As one of the most prevalent serotypes identified in pigs and humans, how <i>S</i>. Derby overcomes acid stress remains unclear. Here, we de novo sequenced the genome of a representative <i>S.</i> Derby strain 14T from our <i>S.</i> Derby strain stock and identified its acid resistance-associated genes using Tn-seq analysis. A total of 35 genes, including those belonging to two-component systems (TCS) (<i>cpxAR</i>), the CRISPR-Cas system (<i>casCE</i>), and other systems, were identified as essential for 14T to survive under acid stress. The results demonstrated that the growth curve and survival ability of Δ<i>cpxA</i> and Δ<i>cpxR</i> were decreased under acid stress, and the adhesion and invasion abilities to the mouse colon cancer epithelial cells (MC38) of Δ<i>cpxR</i> were also decreased compared with the wild type strain, suggesting that the TCS CpxAR plays an essential role in the acid resistance and virulence of <i>S</i>. Derby. Also, CasC and CasE were found to be responsible for acid resistance in <i>S</i>. Derby. Our results indicate that acid stress induces multiple genes’ expression to mediate the acid resistance of <i>S</i>. Derby and enhance its pathogenesis during an infection.
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