Multi-targeting oligopyridiniums: Rational design for biofilm dispersion and bacterial persister eradication.

[Display omitted] • OG c3 exhibits broad-spectrum anti-biofilm activity by concurrently targeting bacterial membrane lipids, DNA, and proteins. • OG c3 ′s unique alternating amphiphilic structure facilitates penetration into the dense extracellular biofilm matrix. • OG c3 effectively eliminates biofilms and exerts synergistic effects with Vancomycin. • The potent anti-biofilm capabilities of OG c3 against drug-resistant bacteria are validated through robust in vitro and in vivo evaluations. The development of effective antibacterial drugs to combat bacterial infections, particularly the biofilm-related infections, remains a challenge. There are two important features of bacterial biofilms, which are well-known critical factors causing biofilms hard-to-treat in clinical, including the dense and impermeable extracellular polymeric substances (EPS) and the metabolically repressed dormant and persistent bacterial population embedded. These characteristics largely increase the difficulty for regular antibiotic treatment due to insufficient penetration into EPS. In addition, the dormant bacteria are insensitive to the growth-inhibiting mechanism of traditional antibiotics. Herein, we explore the potential of a series of new oligopyridinium-based oligomers bearing a multi-biomacromolecule targeting function as the potent bacterial biofilm eradication agent. These oligomers were rationally designed to be "charge-on-backbone" that can offer a special alternating amphiphilicity. This novel and unique feature endows high affinity to bacterial membrane lipids, DNAs as well as proteins. Such a broad multi-targeting nature of molecules not only enables its penetration into EPS, but also plays vital roles in the bactericidal mechanism of action that is highly effective against dormant and persistent bacteria. Our in vitro , ex vivo , and in vivo studies demonstrated that OP c3 , one of the most effective derivatives, was able to offer excellent antibacterial potency against a variety of bacteria and effectively eliminate biofilms in zebrafish models and mouse wound biofilm infection models. [ABSTRACT FROM AUTHOR]