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

Abstract

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.

Synthesis and in Silico Study of Novel Benzisoxazole‐Chromene Derivatives as Potent Inhibitors of Acetylcholinesterase: Metal‐Free Site‐Selective C−N Bond Formation via Aza‐Michael Reaction

“…no changes to the reaction (Table 1, entry 3). This screening was proven to be successful at 60 °C (2-4 h) under the same reagent conditions, given 4-(piperidin-4-yl)benzo[d]isoxazole-3-formylchromene 4 a (Table 1, entries [4][5][6].…”

“…[1] Importantly, 6-fluoro-3-(piperidin-4-yl)benzo [d]isoxazole(3 a) is also known for its various therapeutic values in neoplasm(malignancy), HIV(as anti-retrovirals), [2] as antiinflammatories [3] and in anti-microbial properties. [4] Compounds containing amide bonds, benzoisoxazoles, chromenes, and fluorine atom substitution can change the chemical properties, bio-availability, and biological activities of drugs, [5] which are currently used in disease treatment today. These drug candidates can be used to treat depression, inflammation, malaria, psychosis (Risperidone is an antipsychotic drug used to treat schizophrenia), as antivirals, and as a substitute for steroids [6][7][8][9] (Figure 1).…”

Screening the PRISM library against Staphylococcus aureus reveals a sesquiterpene lactone from Liriodendron tulipifera with inhibitory activity

“…Additionally, we will continue to search for antibacterial components from magnolias and other botanical specimens. 36 and in accordance with Clinical Laboratory Standards Institute (CLSI) standards. 37,38 Staphylococcus aureus DSM 1104 was obtained from the American Type Culture Collection (ATCC 25923™).…”

“…Minimum inhibitory concentrations (MICs) were determined in duplicate by broth microdilution in LB medium as previously described, 36 and in accordance with Clinical Laboratory Standards Institute (CLSI) standards. 37,38 Staphylococcus aureus DSM 1104 was obtained from the American Type Culture Collection (ATCC 25923™).…”

Screening the PRISM Library against Staphylococcus aureus Reveals a Sesquiterpene Lactone from Liriodendron tulipifera with Inhibitory Activity

“…MICs were determined in duplicate by broth microdilution in a LB medium as previously described and in accordance with Clinical Laboratory Standards Institute (CLSI) standards. , S. aureus DSM 1104 was obtained from the American Type Culture Collection (ATCC 25923).…”