A rational strategy to optimize photodrugs by Molecular Dynamics simulations for killing drug-resistant Gram-negative bacteria

Antimicrobial resistance has become a major threat to human health, particularly for Gram-negative bacteria such as Acinetobacter baumannii and Klebsiella pneumoniae. Disruption of membrane integrity is regarded as a promising antimicrobial strategy that does not induce distinct drug resistance, while increasing the internalization of drug doses and mitigating efflux mechanisms. In this study, relying on molecular dynamics (MD) simulations to optimize and confirm the membrane-disrupting activity of photodrugs, we fabricated a series of monomeric (TC_n) and dimeric (TC_nT) photodrugs (n = 4, 8, 12, and 16), with different alkyl chain lengths, enabling their differing bacterial membrane rupture capabilities of inherent. Notably, based on MD simulations and in vitro experiments, TC₈T exhibited enhanced antibacterial efficacy against multiple drug-resistant Gram-negative strains upon white light irradiation, including clinically difficult-to-treat strains. More importantly, TC₈T demonstrated robust antimicrobial activity and promoted tissue reconstruction in murine models of wound infection and post-tumor-resection mixed infections.