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

• Published in: Journal of antibiotics Vol. 74; no. 6; pp. 370 - 380
• Main Authors: Deering, Robert W., Whalen, Kristen E., Alvarez, Ivan, Daffinee, Kathryn, Beganovic, Maya, LaPlante, Kerry L., Kishore, Shreya, Zhao, Sijing, Cezairliyan, Brent, Yu, Shen, Rosario, Margaret, Mincer, Tracy J., Rowley, David C.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2021; Nature Publishing Group
• Subjects: 631/154/436/108; 631/326/22/1290; Acinetobacter baumannii - drug effects; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - metabolism; Anti-Bacterial Agents - pharmacology; Antibacterial agents; Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - chemistry; Bacterial Proteins - metabolism; Bacteriology; Biomedical and Life Sciences; Bioorganic Chemistry; Bradyrhizobium - metabolism; Drug Antagonism; Drug resistance; Drug Resistance, Multiple, Bacterial - drug effects; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Life Sciences; Medicinal Chemistry; Microbial Sensitivity Tests; Microbiology; Molecular Docking Simulation; Molecular Structure; Organic Chemistry; Oxo-Acid-Lyases - antagonists & inhibitors; Oxo-Acid-Lyases - chemistry; Oxo-Acid-Lyases - metabolism; Parabens - pharmacology; Pathogens; Pseudomonas aeruginosa - drug effects
• ISSN: 0021-8820; 1881-1469
• DOI: 10.1038/s41429-021-00412-7

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.