Expand and Sensitize: Guanidine‐Functionalized Exopolysaccharide Nanoparticles Cause Bacterial Cell Expansion and Antibiotic Sensitization

Abstract Conventional antibacterial agents and mechanisms are frequently observed to be ineffective due to the evolution of bacteria to the strains with stronger antibiotic resistance, and hence developing alternative antibacterial materials and mechanisms is urgently needed. Here, guanidine‐functionalized exopolysaccharide (EPS) nanoparticles (termed EPGNs) with durable antibacterial and antibiofilm activities are developed. Very interestingly, the EPGNs obtained by the reaction of EPS, epichlorohydrin, and polyhexamethylene guanidine hydrochloride exhibit an unconventional antibacterial mechanism, i.e., they can induce substantial bacterial cell expansion by upregulating the SulA and DicB proteins that are responsible for cell division inhibition, along with the increase of reactive oxygen species production, bacterial cell surface disruption, and bacterial ribosomal RNA degradation. The transcriptome analysis reveals that EPGNs can hinder cell motility, induce loss of cell integrity, decrease the resistance of bacteria to oxidative stress, and finally lead to cell death. Moreover, EPGNs can effectively accelerate the bacteria‐infected wound healing. This work provides the first example that nanomaterials can cause bacterial cell expansion by affecting intracellular structures and inhibiting cell division, and it may inspire other researchers to investigate the effect of antibacterial materials on the change of bacterial volume and design unconventional antibacterial materials/strategies.