High expression of drug efflux pump makes antibiotics ineffective against bacteria, leading to drug-resistant strains and even the emergence of “superbugs”. Herein, we design and synthesize a dual functional o-nitrobenzene (NB)-modified conjugated oligo-polyfluorene vinylene (OPFV) photosensitizer, OPFV-NB, which can depress efflux pump activity and also possesses photodynamic therapy (PDT) for synergistically overcoming drug-resistant bacteria. Upon light irradiation, the OPFV-NB can produce aldehyde active groups to covalently bind outer membrane proteins, such as tolerant colicin (TolC), blocking drug efflux of bacteria. The minimum inhibitory concentration of antibiotic model chloramphenicol (CHL) is reduced about 64 times, significantly resensitizing drug-resistant bacteria to antibiotics. Also, the probe can produce highly efficient reactive oxygen species (ROS) under light irradiation. Consequently, the unimolecular OPFV-NB-based system demonstrates insusceptibility to antibiotic resistance while maintaining significant antimicrobial effects (100%) against drug-resistant bacteria. More importantly, in vivo assays corroborate that the combined system greatly accelerates wound healing by eradicating the bacterial population, dampening inflammation, and promoting angiogenesis. Overall, the OPFV-NB not only counteracts antibiotic resistance but also holds tremendous PDT efficiency, which provides a promising therapeutic strategy for combating drug-resistant bacteria and treating bacteria-infected wounds.
Yingying Qian,Minggen Cheng,Lin Lai,Jing Zhou,Gerben J. Zylstra,Xing Huang
Overuse of the amphenicol antibiotics chloramphenicol (CHL) and thiamphenicol (TAP) poses a great threat to ecosystem safety and human health. The strain, Nocardioides sp. LMS-CY, Nocardioides sp. QY071 and Nocardioides sp. L-11A, classified as a gram-positive actinomycete, harbours a complete CHL metabolic pathway. However, the metabolic genes (clusters) involved in the entire pathway in gram-positive actinomycetes are still limited. Here, chlOR LMS , chlOR QY071 and chlOR L-11A completely from the actinomycete Nocardioides spp. were found to act on the C 1 -OH of the CHL/TAP side chain, directly converting CHL/TAP to 4-nitrobenzaldehyde (PNBD)/4-methylsulfonyl benzaldehyde (PMBD) and transforming PNBD/PMBD into 4-nitrobenzyl alcohol (PNBM)/4-methylsulfonyl phenyl methanol (PMBM). Furthermore, oxidoreductases can transform PNBM into 4-nitrobenzoate (PNBA). The oxidoreductases ChlOR LMS , ChlOR QY071 and ChlOR L-11A were all classified as cellobiose dehydrogenases from the glucose methanol choline (GMC) family. Based on the Swiss-Prot database, ChlOR QY071 exhibited a lower identity (27.12%–35.10% similarity) with the reported oxidoreductases. Enzymatic and molecular docking analyses showed that ChlOR QY071 and ChlOR L-11A from the two similar genomes were remarkably more effective in metabolizing CHL than ChlOR LMS . Overall, the detailed resistance mechanism of CHL/TAP by actinomycete strains isolated from soil and livestock manure will provide insights into the occurrence of CHL/TAP resistance genes in the environment, resistance risk and bioremediation of CHL/TAP-contaminated environments.
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