Bacteria infected cells acting as “Trojan horses” not only protect bacteria from antibiotic therapies and immune clearance, but also increase the dissemination of pathogens from the initial sites of infection. Antibiotics are hard and insufficient to treat such hidden internalized bacteria, especially multidrug‐resistant (MDR) bacteria. Herein, aggregation‐induced emission luminogens (AIEgens) such as N,N‐diphenyl‐4‐(7‐(pyridin‐4‐yl) benzo [c] [1,2,5] thiadiazol‐4‐yl) aniline functionalized with 1‐bromoethane (TBP‐1) and (3‐bromopropyl) trimethylammonium bromide (TBP‐2) (TBPs) show potent broad‐spectrum bactericidal activity against both extracellular and internalized Gram‐positive pathogens. TBPs trigger reactive oxygen species (ROS)‐mediated membrane damage to kill bacteria, regardless of light irradiation. TBPs effectively kill bacteria without the development of resistance. Additionally, such AIEgens activate mitochondria dependent autophagy to eliminate internalized bacteria in host cells. Compared to the routinely used vancomycin in clinic, TBPs demonstrate comparable efficacy against methicillin‐resistant Staphylococcus aureus (MRSA) in vivo. The studies suggest that AIEgens are promising new agents for the treatment of MDR bacteria associated infections.

The acquisition of resistance to one antibiotic sometimes leads to collateral sensitivity to a second antibiotic. Here, we show that vancomycin resistance in Enterococcus faecium is associated with a remarkable increase in susceptibility to pleuromutilin antibiotics (such as lefamulin), which target the bacterial ribosome. The trade-off between vancomycin and pleuromutilins is mediated by epistasis between the van gene cluster and msrC, encoding an ABC-F protein that protects bacterial ribosomes from antibiotic targeting. In mouse models of vancomycin-resistant E. faecium colonization and septicemia, pleuromutilin treatment reduces colonization and improves survival more effectively than standard therapy (linezolid). Our findings suggest that pleuromutilins may be useful for the treatment of vancomycin-resistant E. faecium infections.

The overuse of antibiotics and the scarcity of new drugs have led to a serious antimicrobial resistance crisis, especially for multi-drug resistant (MDR) Gram-negative bacteria. In the present study, we investigated the antimicrobial activity of a marine antibiotic equisetin in combination with colistin against Gram-negative bacteria and explored the mechanisms of synergistic activity. We tested the synergistic effect of equisetin in combination with colistin on 23 clinical mcr-1 positive isolates and found that 4 µg/mL equisetin combined with 1 µg/mL colistin showed 100% inhibition. Consistently, equisetin restored the sensitivity of 10 species of mcr-1 positive Gram-negative bacteria to colistin. The combination of equisetin and colistin quickly killed 99.9% bacteria in one hour in time-kill assays. We found that colistin promoted intracellular accumulation of equisetin in colistin-resistant E. coli based on LC-MS/MS analysis. Interestingly, equisetin boosted ROS accumulation in E. coli in the presence of colistin. Moreover, we found that equisetin and colistin lost the synergistic effect in two LPS-deficient A. baumannii strains. These findings suggest that colistin destroys the hydrophobic barrier of Gram-negative bacteria, facilitating equisetin to enter the cell and exert its antibacterial effect. Lastly, equisetin restored the activity of colistin in a G. mellonella larvae infection model. Collectively, these results reveal that equisetin can potentiate colistin activity against MDR Gram-negative bacteria including colistin-resistant strains, providing an alternative approach to address Gram-negative pathogens associated with infections in clinics.

Mammalian cells act as reservoirs of internalized bacteria to circumvent extracellular antibacterial compounds, resulting in relapse and reinfection diseases. The intracellular persistence of Staphylococcus aureus renders most traditional antibiotics useless, due to their inadequate subcellular accumulation. To replenish our antibiotic arsenal, we found that a marine-derived compound, equisetin, efficiently eliminates intracellular S. aureus by potentiating the host autophagy and inducing mitochondrial-mediated ROS generation to clear the invading S. aureus. The remarkable anti-infection activity of equisetin was validated in a peritonitis-infected mouse model. The marine product equisetin utilizes a unique dual mechanism to modulate the host–pathogen interaction in the clearance of intracellular bacteria. Thus, equisetin is an inspiring host-acting candidate for overcoming intracellular pathogens.