Recently, a series of novel amide derivatives have been reported by Professor Cui Zining's team from the Group Microbiology Research Center and the National Key Laboratory of Green Pesticide at South China Agricultural University. These derivatives effectively reduce the pathogenicity of Pseudomonas aeruginosa by inhibiting its quorum sensing system, elucidating their mechanism of action and targets. The related findings have been published online in the European Journal of Medicinal Chemistry.
Pseudomonas aeruginosa is a significant opportunistic human pathogen, and its increasing antibiotic resistance poses a serious threat to public health. Quorum sensing (QS) is one of the major discoveries in microbiology in recent years. At its core, QS involves communication among individual pathogenic bacteria cells, which produce and respond to small molecule chemical signals, coordinating collective responses to hosts and the external environment, including establishing infection and antibiotic production.
The discovery of this system provides a new entry point for understanding the pathogenic regulation mechanisms of bacteria and developing new disease control strategies. QS systems are widespread and common potential targets for developing novel antimicrobial drugs. Although certain amide compounds have been reported to inhibit bacterial growth, research on their specific inhibitory effects on bacterial quorum sensing systems is relatively limited.
In this study, Professor Cui Zining's team designed and synthesized a series of novel amide derivatives. Bioactivity evaluations showed that compounds A9 and B6 significantly inhibited the expression of key genes in the QS systems, such as lasB, rhlA, and pqsA, in Pseudomonas aeruginosa PAO1, effectively reducing the production of various important virulence factors. Moreover, compound A9 also reduced the pathogenicity of PAO1 against larvae of the greater wax moth. Furthermore, the mechanisms of action and targets of these compounds were further studied using real-time fluorescence quantitative PCR, surface plasmon resonance (SPR), and molecular docking.
Experimental results demonstrated that compound A9 could bind to important transcriptional regulatory factors, LasR and PqsR, in the QS system of Pseudomonas aeruginosa, especially with PqsR, effectively inhibiting the QS system of Pseudomonas aeruginosa. These findings suggest that amide derivatives A9 and B6, as novel QS inhibitors of Pseudomonas aeruginosa, have the potential for further development.
The research findings provide a new strategy and means for controlling the virulence and pathogenicity of Pseudomonas aeruginosa.
The aforementioned research received funding from the National Natural Science Foundation, the Guangdong Province Distinguished Youth Fund, and the Guangdong Province Excellent Young Talents International Training Program.
Related paper information: https://doi.org/10.1016/j.ejmech.2024.116410
