Multisensory integration of a host metabolite coordinates bacterial predation of macrophages

Chemical communication across kingdoms underpins infection, yet how pathogens actively decode host signals to launch coordinated attacks remains a fundamental mystery. Here, we identify the long-sought mammalian autoinducer-2 mimic as the metabolite mesifurane and demonstrate that the enteric pathogen Yersinia pseudotuberculosis hijacks it to execute a precise "sense, arm and recruit" offensive program. This program is governed by a dedicated multisensory integration circuit: the chemoreceptor YcrA directs targeted chemotaxis, the NarX-NarP two-component system licenses assembly of the type VI secretion system (T6SS) for killing, and derepression of CusR amplifies endogenous bacterial signaling to recruit reinforcements. This circuit is essential for gut colonization and virulence in mice. Remarkably, the core sensory logic is functionally conserved across diverse bacterial families, including multidrug-resistant Escherichia coli and Acinetobacter baumannii. Capitalizing on this conserved vulnerability, we designed a peptide antagonist that disrupts YcrA. This agent disorients pathogen chemotaxis, rescues macrophages from apoptosis, and, crucially, provides significant survival benefit in mice infected with multidrug-resistant isolates. Our work establishes multisensory integration of a host metabolite as a new paradigm for virulence orchestration and, going beyond mechanism, validates the targeting of pathogen perception as a broad-spectrum anti-infective strategy to circumvent conventional resistance mechanisms.