A multi-barrier defence strategy using plant-derived antifungals against mycotoxigenic fungi in livestock feed

Mycotoxigenic fungi, principally Aspergillus, Fusarium, and Penicillium spp. contaminate 60-80% of global feed commodities and cause multi-billion-dollar losses through animal health impairment, reduced productivity, and food chain carry-over. Despite decades of reliance on synthetic antifungals (azoles, polyenes, echinocandins), the emergence of resistant strains and growing regulatory pressure demand fundamentally different solutions. Existing reviews have catalogued plant-derived phytochemicals as promising alternatives yet have failed to provide an integrated, mechanistically grounded, and practically deployable framework that (i) explains why phytochemicals overcome synthetic resistance, (ii) ranks candidate compounds according to translational readiness, and (iii) guides rational multi-component formulation. This review addresses those gaps by introducing three integrative conceptual frameworks proposed for feed-system applications. The Multi-Barrier Phytogenic Defence (MBPD) Framework, which conceptualises antifungal action as five overlapping but mechanistically distinct barriers- specifically, membrane disruption, mycotoxin-gene silencing, oxidative equilibrium perturbation, enzymatic cascade interference, and signal-transduction blockade explains how simultaneous engagement of multiple barriers makes resistance evolution geometrically less probable than with single-target drugs. A Resistance-Indexed Phytochemical Selection (RIPS) model that scores candidate compounds against six criteria (multi-target coverage, ergosterol independence, efflux-pump evasion, biofilm penetration, generally recognized as safe (GRAS) status, and stability in feed matrices) to produce a prioritised shortlist for formulators. A Translational Readiness Score (TRS) applicable across the pipeline from in-vitro evidence to commercial feed inclusion, addressing the persistent gap between laboratory efficacy and practical livestock outcomes. These frameworks are validated against published minimum inhibitory concentration (MIC) data, gene-expression studies, and in-vivo trials, and are used to re-evaluate the evidence base for key compounds including thymol, eugenol, cinnamaldehyde, citral, curcumin, and resveratrol. These six compounds were selected because they represent the highest-scoring candidates under the RIPS model and collectively illustrate the full range of MBPD barrier engagement; the rationale for this selection is detailed in Sects. 5 and 6. The review concludes with a research agenda and a recommendation for an evidence-based regulatory pathway that, taken together, offer a roadmap for sustainable mycotoxin control in global feed systems.