Fatty acid synthase-II is required for the synthesis of mycolic acid and essential for pathogenicity of Nocardia seriolae.

Nocardia seriolae is the etiological agent of fish nocardiosis. Fatty acid synthase type II (FAS-II) system is involved in the biosynthesis of mycolic acid, a key virulence factor of N. seriolae. In this study, genes associated with mycolic acid biosynthesis within the FAS-II system (MabA, HadAB, InhA and KasA) were identified in the wild-type strain ZJ0503. Targeted knockout of these FAS-II enzyme genes yielded the mutants ΔMabA, ΔHadAB, ΔInhA and ΔKasA, which exhibited loss of acid-fast staining and a complete absence of mycolic acid derivatives. Virulence of these mutants was significantly attenuated in snakehead (Channa argus), with LD50 values at 6.90-, 8.00-, 8.07- and 7.16-fold higher than that of the wild-type strain, and they showed a markedly reduced ability to induce foam cell formation and apoptosis in macrophages compared to the wild-type strain. In fish infected with the wild-type strain, significant upregulation of pro-inflammatory genes and prominent granuloma formation were observed in immune tissues, whereas infection with mutants resulted in subdued inflammatory responses and an absence of granulomatous pathology. Collectively, these findings suggest that targeting FAS-II enzymes to inhibit mycolic acid synthesis in N. seriolae could represent a promising therapeutic strategy for controlling and treating fish nocardiosis in the future.