Abstract

Background: Corallopyronin A (CorA) is a bacterial RNA polymerase inhibitor that binds a site distinct from rifamycins, but its activity across the ESKAPEE pathogen panel and its translational potential remain incompletely defined. Methods: CorA activity was evaluated against representative ESKAPEE pathogens using broth microdilution assays ± polymyxin B nonapeptide (PMBN). Activity was benchmarked against rifampin (Rif). Resistance, cross-resistance, serum activity, in vivo efficacy in the Galleria mellonella wax moth larva model, and biofilm disruption were assessed. Results: CorA inhibited Acinetobacter baumannii (minimal inhibitory concentration [MIC] = 16–32 µg/mL), including MDR isolates, with susceptibility enhanced 4–32-fold by efflux disruption or membrane permeabilization. In contrast, most other Gram-negative ESKAPEE pathogens required PMBN for activity, while Gram-positive organisms were intrinsically susceptible. Rif was consistently more potent than CorA across the panel. Rif-resistant A. baumannii and Klebsiella pneumoniae remained fully susceptible to CorA, confirming the absence of cross-resistance. Fractional inhibitory concentration (FIC) index analysis revealed pharmacological indifference between CorA and Rif, with no synergy or antagonism detected. CorA activity was abolished in 50% serum conditions and was not restored by PMBN, consistent with serum sequestration; no efficacy was observed in a G. mellonella infection model at doses up to 20 mg/kg despite Rif demonstrating significant protection. Notably, CorA reduced established A. baumannii biofilms by ∼3–4 log colony-forming units per mL (CFU/mL) across concentrations ≥4× MIC after 24 h of treatment. Conclusions: CorA exhibits selective activity against A. baumannii and retains efficacy against Rif-resistant strains. While high serum binding reduces in vitro activity and efficacy was not observed in the G. mellonella model at a lower dose than in other in vivo models, established in vivo activity against other pathogens demonstrates that serum binding does not preclude therapeutic utility. These findings highlight both the translational considerations for CorA against ESKAPEE pathogens and potential niches for its application, including filarial nematodes, biofilm-associated infections and combination strategies.

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