A rationally designed mannosylated amphiphilic pillar[5]arene (Man@AP5) self-assembles into supramolecular vesicles with encapsulated vancomycin (Man@AP5-Van), enhancing vancomycin's antibacterial efficacy against intracellular MRSA.

There is an urgent need to discover new antibiotics and improve the efficacy of known antibiotics against Gram-negative bacteria. “Trojan horse” conjugates are novel and promising antibiotics. Herein we report the design and synthesis of vitamin-B12–ampicillin conjugates, which exhibited more than 500 times improved activity against Escherichia coli compared with ampicillin itself. Our studies demonstrate that the vitamin-B12 uptake pathway could be employed for effective antibiotic delivery and efficacy enhancement.

Drug repurposing is considered a promising strategy to fight antimicrobial resistance (AMR). Methotrexate (Mtx), a classical anticancer drug, could strongly inhibit bacterial dihydrofolate reductase (DHFR). However, its poor permeability into bacteria and potent human cytotoxicity make it unsuitable as an antibacterial. Herein, we reported the conjugation of Mtx with a siderophore to construct "Trojan horse" antibacterials. The most potent conjugate 8 with nanomolar minimum inhibitory concentration (MIC) values exhibited over 1.00 × 10 3 -fold improved activity against Gram-positive Streptococcus pneumoniae (S. pneumoniae) and Gram-negative Yersinia enterocolitica (Y. enterocolitica) compared with Mtx, while possessing 2.31 × 10 3 -fold reduced human cytotoxicity, resulting in 2.08 × 10 6 -fold improvements in the therapeutic index. This proof-of-principle study verifies that siderophore conjugation is an effective strategy for developing new antibacterials from anticancer drugs.

Methicillin-resistant Staphylococcus aureus (MRSA) has led to serious infections, especially in hospitals and clinics, where treatment and prevention have become more difficult due to the formation of biofilms. Owing to biofilm-derived antibiotic tolerance, the currently available traditional antibiotics have failed to treat MRSA infections. Hence, there is a urgent need to develop novel antibiotics for treating life-threatening MRSA infections. Lugdunin (cyclic peptide-1), a nonribosomal cyclic peptide produced by Staphylococcus lugdunensis, exhibits potent antimicrobial activity against MRSA. Amazingly, cyclic peptide-1 and its analogues cyclic peptide-11 and cyclic peptide-14 have the ability to disperse mature MRSA biofilms and show anti-clinical MRSA activity, including MRSA persister cells. In addition, these three cyclic peptide compounds have non-toxicity, lower hemolytic activity and lack of resistance development. Our results indicate that cyclic peptide-1, cyclic peptide-11, and cyclic peptide-14 have great potential as new antimicrobial drug candidates for the treatment of clinical MRSA infections.

Drug repurposing is considered a promising strategy to fight antimicrobial resistance (AMR). Methotrexate (Mtx), a classical anticancer drug, could strongly inhibit bacterial dihydrofolate reductase (DHFR). However, its poor permeability into bacteria and potent human cytotoxicity make it unsuitable as an antibacterial. Herein, we reported the conjugation of Mtx with a siderophore to construct "Trojan horse" antibacterials. The most potent conjugate 8 with nanomolar minimum inhibitory concentration (MIC) values exhibited over 1.00 × 10 3 -fold improved activity against Gram-positive Streptococcus pneumoniae (S. pneumoniae) and Gram-negative Yersinia enterocolitica (Y. enterocolitica) compared with Mtx, while possessing 2.31 × 10 3 -fold reduced human cytotoxicity, resulting in 2.08 × 10 6 -fold improvements in the therapeutic index. This proof-of-principle study verifies that siderophore conjugation is an effective strategy for developing new antibacterials from anticancer drugs.