The study shows that the ClpXP protease is essential for maintaining resistance to cell-envelope targeting antimicrobials in Bacillus anthracis Sterne. Disruption of clpX, clpP1, or clpP2 leads to increased susceptibility to various antimicrobials, including LL-37, nisin, daptomycin, penicillin, and vancomycin. Both clpP1 and clpP2 contribute to resistance, though the effect of clpX disruption is more pronounced.