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Our analyses of population-level genomic data found nimB and gyrA variants are advantageous, as expected for drug resistance mutations. The two mutations were strongly linked, and phylogenetic analyses suggest that strains carrying both mutations spread more rapidly in healthcare settings (Figs. 4b, 5a–f). This hypothesis is consistent with previously published data suggesting that fluroquinolone-resistant C. difficile spread rapidly across continents24,25,26. We found the combination of nimB and gyrA mutations in Clade 2 and to a lesser extent Clade 1 (Figs. 4b, 5a–f). This association could reflect niche specialization among the Clades. Large scale surveys of C. difficile genomic data have identified high rates of carriage of both antimicrobial resistance determinants and toxin genes in Clade 221,59,60. This genetic cargo reflects adaptation of Clade 2 to the antibiotic milieu of health care settings and pathogenicity in human diarrheal disease21,25. Clade 5 is similarly associated with antibiotic resistance and increased virulence59, but we did not identify the nimB-promoter mutation in our sample of Clade 5 isolates (Fig. 5f). Clade 5 antimicrobial resistance determinants reflect the livestock and farming environments that are associated with this Clade21 and absence of the nimB-promoter mutation from this Clade could reflect the distinct antibiotic selection pressures encountered in these environments. It is also possible that the nimB-promoter mutation, and resulting heme-dependent metronidazole resistance, is a human-specific adaptation. Given the small number of Clade 5 isolates included in our analyses, a larger sample size will be required to test this hypothesis. An alternative, but not mutually exclusive, explanation for the observed associations between the nimB-promoter mutation, the gyrA mutation and the Clade 2 genetic background is epistasis, i.e., interactions among genetic loci that affect cell physiology. It is striking that the nimB mutation almost exclusively appears among strains with the gyrA mutation (Fig. 4b). A potential explanation for this phenomenon is that the nimB-promoter mutation and constitutive formation of nimB imposes a metabolic burden and fitness costs that might be ameliorated in strains with the gyrA mutation. However, isogenic 23468 and 23475, which are resistant and susceptible respectively, did not show significant differences in growth rates (Supplementary Fig. 3). On the other hand, Thr82Ile mutation in GyrA either marginally enhances fitness or has no fitness costsIle on Clostridioides difficile fitness. J. Antimicrob. Chemother. 74, 877–884 (2019)." href="/articles/s41467-023-39429-x#ref-CR61" id="ref-link-section-d282361552e2966"61,62. Future studies will be required to determine the extent to which coexisting metronidazole and fluoroquinolone resistance affects C. difficile transmission, using clinically reflective animal and in vitro models./p>70% alignment to the reference./p>Ile on Clostridioides difficile fitness. J. Antimicrob. Chemother. 74, 877–884 (2019)./p>