Polypharmacology of Securidaca longepedunculata Against Multidrug-Resistant Pathogens: Resistance Mechanisms, Novel Scaffolds, and Synergy Mapping

The alarming rise of multidrug-resistant (MDR) bacterial pathogens is a crisis of unprecedented scale confronting Nigeria's healthcare system, with hospitals in all geopolitical zones reporting increasing rates of carbapenem-resistant Enterobacteriaceae and MRSA. Securidaca longepedunculata, a Sahelian shrub used across North Central and North West Nigeria for infections of diverse types, has demonstrated broad-spectrum antibacterial activity in preliminary studies. However, its polypharmacological potential against MDR pathogens, resistance reversal mechanisms, and novel scaffold identity remain unexplored at the depth required for drug development. This research systematically maps the antibacterial polypharmacology of Securidaca longepedunculata root fractions against a panel of 40 characterised MDR clinical isolates from six tertiary hospitals spanning all geopolitical zones, using whole-genome sequencing to characterise resistance determinants. Novel antibacterial scaffolds are isolated by bioassay-guided column chromatography and preparative HPLC, with structural characterisation by 2D-NMR and HRMS. Synergy mapping between plant fractions and last-resort antibiotics is performed using a high-throughput checkerboard platform. Resistance mechanism analysis investigates membrane permeabilisation, efflux pump inhibition, and beta-lactamase inhibitory activity. Three structurally novel compounds including a saponin scaffold with unprecedented connectivity were characterised. Two compounds demonstrated potent MRSA activity (MIC less than 1 ug/mL) and synergistic interaction with vancomycin (FICI less than 0.5). Beta-lactamase inhibitory activity was confirmed in the alkaloid fraction. This research positions Securidaca longepedunculata as a priority species for antibiotic lead development in Nigeria. Keywords: Securidaca longepedunculata, multidrug resistance, polypharmacology, synergy, novel scaffolds