Co-selection for heavy metal and multidrug resistance: Cadmium primes bacterial antibiotic resistance by enhancing intrinsic oxidative stress tolerance.

Antibiotic resistance in bacteria can be shaped by environmental factors, including heavy metal contamination. Cadmium (Cd) can enhance bacterial tolerance against other toxic agents, including antibiotics. In this study, we investigated how Cd exposure influences antibiotic resistance across environmental and host-associated contexts. We demonstrate that chronic Cd contamination in soil (5.8 mg Cd/kg) reshapes bacterial communities, enriching Proteobacteria (32.9-37.1 %) that show increased resistance to both Cd (16 mg/L) and four major antibiotics targeting cell wall synthesis (fosfomycin, D-cycloserine), DNA synthesis (ciprofloxacin), and protein synthesis (gentamicin). Extending these findings to host-associated contexts, we found that over 70 % of the Cd-resistant lactic acid bacteria (82 Cd-resistant strains out of 145 isolates) exhibited resistance to at least one antibiotic. To reinforce these findings, we screened Cd-resistant isolates (31.2 μg/mL Cd) from human skin commensals and identified Dermacoccus nishinomiyaensis. D. nishinomiyaensis showed strong resistance to multiple antibiotics, with enhanced thiol-based detoxification that mitigates Cd-induced oxidative damage and contributes to antibiotic resistance. Finally, using Staphylococcus aureus as a model, we demonstrate that Cd exposure primes bacteria for antibiotic tolerance through the bacillithiol pathway via bshC. Bacillithiol reduces oxidative stress and drives a 10-100-fold increase in persister cell formation and antibiotic tolerance. Collectively, our results reveal mechanisms by which heavy metal exposure drives antibiotic resistance, underscoring the importance of controlling environmental Cd contamination to limit the spread of antibiotic resistant bacteria.