Identification of a bacteria-produced benzisoxazole with antibiotic activity against multi-drug resistant Acinetobacter baumannii.

Autor: Deering RW; Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI, USA., Whalen KE; Department of Biology, Haverford College, Haverford, PA, USA. kwhalen1@haverford.edu., Alvarez I; Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI, USA., Daffinee K; Department of Pharmacy Practice, College of Pharmacy, University of Rhode Island, Kingston, RI, USA.; Infectious Diseases Research Program, Providence Veterans Affairs Medical Center, Providence, RI, USA., Beganovic M; Department of Pharmacy Practice, College of Pharmacy, University of Rhode Island, Kingston, RI, USA.; Infectious Diseases Research Program, Providence Veterans Affairs Medical Center, Providence, RI, USA., LaPlante KL; Department of Pharmacy Practice, College of Pharmacy, University of Rhode Island, Kingston, RI, USA.; Infectious Diseases Research Program, Providence Veterans Affairs Medical Center, Providence, RI, USA., Kishore S; Department of Biology, Haverford College, Haverford, PA, USA., Zhao S; Department of Biology, Haverford College, Haverford, PA, USA., Cezairliyan B; Octagon Therapeutics, Inc., Cambridge, MA, USA., Yu S; Octagon Therapeutics, Inc., Cambridge, MA, USA., Rosario M; Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI, USA., Mincer TJ; Wilkes Honors College and Harbor Branch Oceanographic Institute, Florida Atlantic University, Boca Raton, FL, USA. tmincer@fau.edu., Rowley DC; Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI, USA. drowley@uri.edu.
Jazyk: angličtina
Zdroj: The Journal of antibiotics [J Antibiot (Tokyo)] 2021 Jun; Vol. 74 (6), pp. 370-380. Date of Electronic Publication: 2021 Feb 12.
DOI: 10.1038/s41429-021-00412-7
Abstrakt: The emergence of multi-drug resistant pathogenic bacteria represents a serious and growing threat to national healthcare systems. Most pressing is an immediate need for the development of novel antibacterial agents to treat Gram-negative multi-drug resistant infections, including the opportunistic, hospital-derived pathogen, Acinetobacter baumannii. Herein we report a naturally occurring 1,2-benzisoxazole with minimum inhibitory concentrations as low as 6.25 μg ml -1 against clinical strains of multi-drug resistant A. baumannii and investigate its possible mechanisms of action. This molecule represents a new chemotype for antibacterial agents against A. baumannii and is easily accessed in two steps via de novo synthesis. In vitro testing of structural analogs suggest that the natural compound may already be optimized for activity against this pathogen. Our results demonstrate that supplementation of 4-hydroxybenzoate in minimal media was able to reverse 1,2-benzisoxazole's antibacterial effects in A. baumannii. A search of metabolic pathways involving 4-hydroxybenzoate coupled with molecular modeling studies implicates two enzymes, chorismate pyruvate-lyase and 4-hydroxybenzoate octaprenyltransferase, as promising leads for the target of 3,6-dihydroxy-1,2-benzisoxazole.
Databáze: MEDLINE
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