Conserved vulnerability of SoxR underlies zinc-mediated redox disruption and synergistic killing in Klebsiella pneumoniae

[摘要] ABSTRACTThe escalating threat of antimicrobial resistance in Klebsiella pneumoniae necessitates novel therapeutic vulnerabilities. Here, we identify the redox-sensing regulator SoxR as a specific target of zinc toxicity and reveal that SoxR regulatory networks differ fundamentally even among closely related Enterobacteriaceae. Integrated in vitro and in vivo analyses show that zinc competitively displaces the essential SoxR [2Fe–2S] cluster, causing protein destabilization and functional inactivation. Consequently, bacteria fail to activate the canonical soxS–sodA defense axis, rendering them hypersensitive to vitamin K3-induced superoxide stress. Building on this mechanism, we established a synergistic strategy combining zinc with vitamin K3. This combination elicited potent bactericidal activity against K. pneumoniae (including ciprofloxacin-resistant strains) and Salmonella Typhimurium, with a remarkably low propensity for resistance development. Furthermore, treatment significantly improved survival in a Galleria mellonella acute infection model without detectable host toxicity. Collectively, highlighting SoxR [2Fe–2S] cluster integrity as a critical vulnerability, this work extends metal–redox crosstalk-based antibacterial intervention from Escherichia coli to a clinically important pathogen and provides a conceptual framework for developing redox-targeting therapies against drug-resistant gram-negative bacteria.IMPORTANCEKlebsiella pneumoniae is a major drug-resistant pathogen whose survival in the host depends heavily on its ability to withstand oxidative stress. While the SoxR/SoxS system is well characterized in Escherichia coli, whether SoxR functions similarly in K. pneumoniae and whether it can be selectively targeted have remained unknown. Here, we show that the SoxR regulatory network displays clear species-dependent features: sequence comparison reveals low homology of soxS between the two organisms, and SoxR function cannot be simply interchanged across them. Importantly, we demonstrate for the first time that Zn²+ specifically targets K. pneumoniae SoxR by directly and competitively disrupting its essential [2Fe–2S] cluster, leading to protein instability, loss of redox regulatory function, and heightened sensitivity to oxidative stress. This previously unrecognized metal–redox interference mechanism exposes a conserved biochemical vulnerability in oxidative defense and provides a mechanistic basis for developing nontraditional antibacterial strategies that exploit intrinsic stress-response weaknesses rather than conventional growth targets.

[发布日期] 2026-09-09

[关键词] Klebsiella pneumoniae;SoxR;iron-sulfur cluster;zinc toxicity;oxidative stress;antibacterial synergy