A small molecule interacts with pMAC-derived hydroperoxide reductase and enhances the activity of aminoglycosides

Hui, Zhen1,2; Liu, Shiyi1,2; Cui, Ruiqin1,2; Zhou, Biao1,2; Hu, Chunxia1,2; Zhang, Min1,2; Deng, Qiuyang1,2; Cheng, Shumin1,2; Luo, Yutian2,3; Chen, Huaisheng2,3; Wu, Jinsong2,4; Lu, Yuemei2,4; Liu, Xueyan2,3; Dai, Lingyun1,2; Huang, Wei1,2

2021

10.1038/s41429-020-00401-2

JOURNAL OF ANTIBIOTICS   影响因子和分区

0021-8820

1881-1469

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-beta-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.

SCI

英语

通讯

International Collaborative Research Fund of Shenzhen Science and Technology Innovation Commission[GJHZ201 80413181716797] ; Free Inquiry Fund of Shenzhen Science and Technology Innovation Commission[JCYJ20180305163929948]

Biotechnology & Applied Microbiology ; Immunology ; Microbiology ; Pharmacology & Pharmacy

Biotechnology & Applied Microbiology ; Immunology ; Microbiology ; Pharmacology & Pharmacy

WOS:000608387400001

SPRINGERNATURE

PHARMACOLOGY & TOXICOLOGY

Web of Science

1.Jinan Univ, Bacteriol & Antibacterial Resistance Surveillance, Shenzhen Inst Resp Dis, Shenzhen Peoples Hosp,Clin Med Coll 2, Shenzhen 518020, Guangdong, Peoples R China
2.Southern Univ Sci & Technol, Affiliated Hosp 1, Shenzhen 518020, Guangdong, Peoples R China
3.Jinan Univ, Clin Med Coll 2, Shenzhen Peoples Hosp, Intens Care Unit, Shenzhen 518020, Guangdong, Peoples R China
4.Jinan Univ, Clin Med Coll 2, Shenzhen Peoples Hosp, Dept Clin Lab, Shenzhen 518020, Guangdong, Peoples R China

Hui, Zhen,Liu, Shiyi,Cui, Ruiqin,et al. A small molecule interacts with pMAC-derived hydroperoxide reductase and enhances the activity of aminoglycosides[J]. JOURNAL OF ANTIBIOTICS,2021.

Hui, Zhen.,Liu, Shiyi.,Cui, Ruiqin.,Zhou, Biao.,Hu, Chunxia.,...&Huang, Wei.(2021).A small molecule interacts with pMAC-derived hydroperoxide reductase and enhances the activity of aminoglycosides.JOURNAL OF ANTIBIOTICS.

Hui, Zhen,et al."A small molecule interacts with pMAC-derived hydroperoxide reductase and enhances the activity of aminoglycosides".JOURNAL OF ANTIBIOTICS (2021).