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In Pseudomonas aeruginosa , the orphan two-component sensor SagS contributes both to transition to biofilm formation and to biofilm cells gaining their heightened tolerance to antimicrobials. However, little is known about the identity of the signals or conditions sensed by SagS to induce the switch to the sessile, drug-tolerant mode of growth. Using a modified Biolog phenotype assay to screen for compounds that modulate attachment in a SagS-dependent manner, we identified glucose-6-phosphate to enhance attachment in a manner dependent on the glucose-6-phosphate concentration and SagS. The stimulatory effect was not limited to the attachment since glucose-6-phosphate likewise enhanced biofilm formation and also enhanced the expression of select biofilm marker genes. Moreover, exposure to glucose-6-phosphate coincided with decreased swarming motility but increased cellular cyclic-di-GMP (c-di-GMP) levels in biofilms. No such response was noted for compounds modulating attachment and biofilm formation in a manner independent of SagS. Modulation of c-di-GMP in response to glucose-6-phosphate was due to the diguanylate cyclase NicD, with NicD also being required for enhanced biofilm formation. The latter was independent of the sensory domain of NicD but dependent on NicD activity, SagS, and the interaction between NicD and SagS. Our findings indicate that glucose-6-phosphate likely mimics a signal or conditions sensed by SagS to activate its motile-sessile switch function. In addition, our findings provide new insight into the interfaces between the ligand-mediated two-component system signaling pathway and c-di-GMP levels. IMPORTANCE Pathogens sense and respond to signals and cues present in their environment, including host-derived small molecules to modulate the expression of their virulence repertoire. Here, we demonstrate that the opportunistic pathogen Pseudomonas aeruginosa responds to glucose-6-phosphate. Since glucose-6-phosphate is primarily made available due to cell lysis, it is likely that glucose-6-phosphate represents a cross-kingdom cell-to-cell signal that enables P. aeruginosa to adapt to the (nutrient-poor) host environment by enhancing biofilm formation, cyclic-di-GMP, and the expression of genes linked to biofilm formation in a concentration- and SagS-dependent manner., (Copyright © 2021 Park et al.)