A small molecule interacts with pMAC-derived hydroperoxide reductase and enhances the activity of aminoglycosides.
Zhen HuiShiyi LiuRuiqin CuiBiao ZhouChunxia HuMin ZhangQiuyang DengShumin ChengYutian LuoHuaisheng ChenJinsong WuYuemei LuXueyan LiuLingyun DaiWei HuangPublished in: The Journal of antibiotics (2021)
The threat of antimicrobial resistance calls for more efforts in basic science, drug discovery, and clinical development, particularly gram-negative carbapenem-resistant pathogens. We sought to identify novel antibacterial agents against Acinetobacter baumannii ATCC19606 using whole cell-based screening. A small molecule named 6D1 with the chemical structure of 6-fluorobenzo[d]isothiazol-3(2H)-one was identified and exhibited activity against A. baumannii ATCC19606 strain (minimal inhibitory concentration, MIC = 1 mg l-1). The mutation in the plasmid-derived ohrB gene that encodes a peroxidase was identified in spontaneously resistant mutants. Treatment of the bacteria with 6D1 resulted in increased sensitivity to peroxide, such as tert-butyl hydroperoxide. The binding of 6D1 and OhrB was confirmed by surface plasmon resonance. Interestingly, the MIC of kanamycin and gentamicin against spontaneously resistant mutants decreased. Finally, we identified the effect of 6D1 on enhancing the antibacterial activity of kanamycin and gentamicin, including against New Delhi metallo-β-lactamase (NDM-1)-producing carbapenem-resistant Klebsiella pneumoniae, but not in strains carrying aminoglycosides resistance genes. In this study, we identified a small molecule that suppresses the growth of A. baumannii, interacts with hydroperoxide reductase from A. baumannii ATCC19606 plasmid pMAC, and enhances the antibacterial activity of kanamycin and gentamicin. We propose that peroxidase may be potentially used as a target for aminoglycosides adjuvant development.
Keyphrases
- multidrug resistant
- gram negative
- small molecule
- klebsiella pneumoniae
- acinetobacter baumannii
- drug resistant
- escherichia coli
- antimicrobial resistance
- drug discovery
- protein protein
- silver nanoparticles
- genome wide
- binding protein
- hydrogen peroxide
- crispr cas
- gene expression
- genome wide identification
- public health
- signaling pathway
- mesenchymal stem cells
- single cell
- copy number
- cell therapy
- anti inflammatory
- cystic fibrosis
- dna methylation
- wild type