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Identification of a Bacteria-Produced Benzisoxazole with Antibiotic Activity Against Multi-Drug Resistant Acinetobacter Baumannii

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Identification of a Bacteria-Produced Benzisoxazole with Antibiotic Activity Against Multi-Drug Resistant Acinetobacter Baumannii University of Rhode Island DigitalCommons@URI Pharmacy Practice Faculty Publications Pharmacy Practice 2-2021 Identification of a Bacteria-produced Benzisoxazole with Antibiotic Activity against Multi-drug Resistant Acinetobacter baumannii Robert W. Deering Kristen E. Whalen Ivan Alvarez Kathryn Daffinee University of Rhode Island, [email protected] Maya Beganovic See next page for additional authors Follow this and additional works at: https://digitalcommons.uri.edu/php_facpubs Citation/Publisher Attribution Deering, R.W., Whalen, K.E., Alvarez, I. et al. Identification of a bacteria-produced benzisoxazole with antibiotic activity against multi-drug resistant Acinetobacter baumannii. J Antibiot (2021). https://doi.org/ 10.1038/s41429-021-00412-7 This Article is brought to you for free and open access by the Pharmacy Practice at DigitalCommons@URI. It has been accepted for inclusion in Pharmacy Practice Faculty Publications by an authorized administrator of DigitalCommons@URI. For more information, please contact [email protected]. Authors Robert W. Deering, Kristen E. Whalen, Ivan Alvarez, Kathryn Daffinee, Maya Beganovic, Kerry L. LaPlante, Shreya Kishore, Sijing Zhao, Brent Cezairliyan, Shen Yu, Margaret Rosario, Tracy J. Mincer, and David C. Rowley This article is available at DigitalCommons@URI: https://digitalcommons.uri.edu/php_facpubs/201 The Journal of Antibiotics https://doi.org/10.1038/s41429-021-00412-7 ARTICLE Identification of a bacteria-produced benzisoxazole with antibiotic activity against multi-drug resistant Acinetobacter baumannii 1 2 1 3,4 3,4 Robert W. Deering ● Kristen E. Whalen ● Ivan Alvarez ● Kathryn Daffinee ● Maya Beganovic ● 3,4 2 2 5 5 1 Kerry L. LaPlante ● Shreya Kishore ● Sijing Zhao ● Brent Cezairliyan ● Shen Yu ● Margaret Rosario ● 6 1 Tracy J. Mincer ● David C. Rowley Received: 29 October 2020 / Revised: 21 December 2020 / Accepted: 4 January 2021 © The Author(s) 2021. This article is published with open access 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 μgml−1 against clinical strains of multi-drug resistant A. baumannii and investigate its possible mechanisms of action. This molecule represents a 1234567890();,: 1234567890();,: 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 octaprenyl- transferase, as promising leads for the target of 3,6-dihydroxy-1,2-benzisoxazole. Introduction These authors contributed equally: Robert W. Deering, Kristen E. Whalen Acinetobacter baumannii is a non-fermenting, Gram- Supplementary information The online version contains negative member of the Gammaproteobacteria commonly supplementary material available at https://doi.org/10.1038/s41429- implicated in nosocomial sepsis, wound infections, and 021-00412-7. ventilator-associated pneumonia [1]. The World Health * Kristen E. Whalen Organization recognizes antibiotic resistance as one of the [email protected] three greatest threats to human health, and recently classi- * Tracy J. Mincer fied carbapenem-resistant A. baumannii as one of the most [email protected] urgent threats, calling for a renewed investment in antibiotic * David C. Rowley development [2]. A. baumannii tenacity in hospitals is [email protected] enhanced both by its ability to develop antibiotic resistance and capacity to survive on surfaces, including skin, for 1 Department of Biomedical and Pharmaceutical Sciences, College several days [3]. A. baumannii can also spread via aero- of Pharmacy, University of Rhode Island, Kingston, RI, USA solization, promoting this pathogen’s ability to easily 2 Department of Biology, Haverford College, Haverford, PA, USA colonize new environments [4–6]. A. baumannii is a 3 Department of Pharmacy Practice, College of Pharmacy, member of the so-called ‘ESKAPE’ pathogens [7] and has University of Rhode Island, Kingston, RI, USA garnered significant attention due to its propensity to cause 4 Infectious Diseases Research Program, Providence Veterans wound infections in U.S. service members who served in Affairs Medical Center, Providence, RI, USA Iraq and Afghanistan [8]. Alarmingly, intensive care unit 5 Octagon Therapeutics, Inc., Cambridge, MA, USA patients contracting A. baumannii infections have a high 6 Wilkes Honors College and Harbor Branch Oceanographic mortality rate (>50%), complicated by the fact that new Institute, Florida Atlantic University, Boca Raton, FL, USA pan-drug resistant (PR) strains of A. baumannii with R. W. Deering et al. resistance to all chemotherapeutic treatment options have from 72 l of B158 microbial culture resulted in the isolation now emerged [1, 8–10]. Carbapenems, typically in combi- of compound 1. nation with other antimicrobial agents (e.g., the polypeptide Compound 1 was isolated as an amorphous white pow- colistin) are a commonly utilized treatment option for multi- der. An [M − H]− ion of 150.0204 using HRESIMS indi- 1 drug resistant (MDR) A. baumannii, but it is cated a molecular formula of C7H5NO3. HNMR estimated that more than half of MDR strains are now resonances at δH 7.49, 6.75, and 6.67 as well as the mole- carbapenem-resistant and colistin has significant tox- cular formula suggested 1 to be 3,6-dihydroxy-benzisox- icological and dosing concerns [1, 11, 12]. With the lack of azole [35]. Because only 1 mg of compound 1 was isolated new antibiotics in the drug discovery pipeline to treat Gram- from 14.1 g of crude extract, 3,6-dihydroxy-benzisoxazole negative infections, coupled with accelerated evolution was synthesized (Fig. S1) and determined to be identical to of antibiotic resistance, it is imperative that new anti- the natural product by NMR spectroscopy (Table S1) [35]. bacterial drugs for treating A. baumannii infections be The synthetic derivative of compound 1 showed potent developed [13]. antimicrobial activity against Escherichia coli MDR strains Although uncommonly reported from natural sources, AG102, MG1655 ΔBC/pABM, and MG1655 ΔBC/pXYM benzisoxazole scaffolds are well represented in pharmacol- with an MIC between 0.31 and 0.63 µg ml−1. ogy, having shown significant importance in anti-HIV [14], antimicrobial [15–18], antipsychotic [19, 20], anti- 3,6-Dihydroxy-1,2-benzisoxazole (1) inhibits the inflammatory [17, 21, 22], antioxidation [17, 23], anticancer growth of clinically relevant strains of A. baumanii [23–26], anticonvulsant [27] and antidiabetic [28, 29] research. Moreover, 1,2-benzisoxazole derivatives, which Compound 1 was previously reported to possess growth include zonisamide, risperidone, paliperidone, and iloper- inhibitory effects against Gram-negative pathogenic bac- idone, are all FDA approved and currently in use for epilepsy, teria, but not Gram-positives [36]. Because this prior testing mood disorders, and schizophrenia, respectively [30–33]. was completed more than 30 years ago and did not include Herein we report the identification of 3,6-dihydroxy-1,2- A. baumannii, we tested 1 for antibacterial activity against a benzisoxazole (1), a potent antibiotic against A. baumannii panel of four clinically relevant A. baumannii strains produced by a marine bacterium identified as a Bradyrhizo- (Table S2). Two strains (L1051 and NR-13382) were bium denitrificans. A series of synthetically prepared analogs classified as carbapenem-resistant A. baumannii (CRAB) define key structural features for the antibacterial effects. We and as multi-drug resistant (MDR) organisms by having further provide evidence suggesting the mechanism of action non-susceptibility to one or more agents in three or more (MOA) of 3,6-dihydroxy-1,2-benzisoxazole. In discovering antimicrobial categories using previously published guide- 4-hydroxybenzoate (4-HB)’s ability to reverse the anti- lines [37, 38]. Minimum inhibitory concentrations (MICs) bacterial property of 1, we investigate two possible 4-HB- were determined to be in the range of 6.25 μgml−1 to 50 μg utilizing target enzymes, chorismate pyruvate-lyase (CPL) ml−1 with the most potent antibacterial effects against the and 4-HB octaprenyltransferase. MDR strains NR-13382 and L1051 (6.25 and 12.5 μgml−1, respectively). While the MICs for these clinical strains were measured in Muller-Hinton broth (MHB), additional MIC Results testing was pursued using both MHB and DM01, a defined minimal medium supplemented with sodium pyruvate as a Bioassay-guided fractionation and dereplication of carbon source. We hypothesized that nutrient replete media 3,6-dihydroxy-1,2-benzisoxazole could contain compounds that antagonized the antibiotic activity of 1, which could provide insight into compound Crude organic extract from the exudate of B. denitrificans 1’s MOA. Interestingly,
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