@article{hubble_bartholomew_weig_brackett_barlock_mattingly_nemeth_melander_melander_2020, title={Augmenting the Activity of Macrolide Adjuvants against Acinetobacter baumannii}, volume={11}, ISSN={["1948-5875"]}, DOI={10.1021/acsmedchemlett.0c00276}, abstractNote={Approximately 1.7 million Americans develop hospital associated infections each year, resulting in more than 98,000 deaths. One of the main contributors to such infections is the Gram-negative pathogen Acinetobacter baumannii. Recently, it was reported that aryl 2-aminoimidazole (2-AI) compounds potentiate macrolide antibiotics against a highly virulent strain of A. baumannii, AB5075. The two lead compounds in that report increased clarithromycin (CLR) potency against AB5075 by 16-fold, lowering the minimum inhibitory concentration (MIC) from 32 to 2 μg/mL at a concentration of 10 μM. Herein, we report a structure-activity relationship study of a panel of derivatives structurally inspired by the previously reported aryl 2-AI leads. Substitutions around the core phenyl ring yielded a lead that potentiates clarithromycin by 64- and 32-fold against AB5075 at 10 and 7.5 μM, exceeding the dose response of the original lead. Additional probing of the amide linker led to the discovery of two urea containing adjuvants that suppressed clarithromycin resistance in AB5075 by 64- and 128-fold at 7.5 μM. Finally, the originally reported adjuvant was tested for its ability to suppress the evolution of resistance to clarithromycin over the course of nine consecutive days. At 30 μM, the parent compound reduced the CLR MIC from 512 to 2 μg/mL, demonstrating that the original lead remained active against a more CLR resistant strain of AB5075.}, number={9}, journal={ACS MEDICINAL CHEMISTRY LETTERS}, author={Hubble, Veronica B. and Bartholomew, Kyle R. and Weig, Alexander W. and Brackett, Sara M. and Barlock, Samantha L. and Mattingly, Anne E. and Nemeth, Ansley M. and Melander, Roberta J. and Melander, Christian}, year={2020}, month={Sep}, pages={1723–1731} }
 @article{hubble_hubbard_minrovic_melander_melander_2019, title={Using Small-Molecule Adjuvants to Repurpose Azithromycin for Use against Pseudomonas aeruginosa}, volume={5}, ISSN={["2373-8227"]}, DOI={10.1021/acsinfecdis.8b00288}, abstractNote={A major contributor to fatalities in cystic fibrosis (CF) patients stems from infection with opportunistic bacterium Pseudomonas aeruginosa. As a result of the CF patient's vulnerability to bacterial infections, one of the main treatment focuses is antibiotic therapy. However, the highly adaptive nature of P. aeruginosa, in addition to the intrinsic resistance to many antibiotics exhibited by most Gram-negative bacteria, means that multi-drug-resistant (MDR) strains are increasingly prevalent. This makes the eradication of pseudomonal lung infections nearly impossible once the infection becomes chronic. New methods to treat pseudomonal infections are greatly needed in order to eradicate MDR bacteria found within the respiratory tract, and ultimately better the quality of life for CF patients. Herein, we describe a novel approach to combatting pseudomonal infections through the use of bis-2-aminoimidazole adjuvants that can potentiate the activity of a macrolide antibiotic commonly prescribed to CF patients as an anti-inflammatory agent. Our lead bis-2-AI exhibits a 1024-fold reduction in the minimum inhibitory concentration of azithromycin in vitro and displays activity in a Galleria mellonella model of infection.}, number={1}, journal={ACS INFECTIOUS DISEASES}, author={Hubble, Veronica B. and Hubbard, Brittany A. and Minrovic, Bradley M. and Melander, Roberta J. and Melander, Christian}, year={2019}, month={Jan}, pages={141–151} }
 @article{stephens_hubble_ernst_hoek_melander_cavanagh_melander_2016, title={Potentiation of Francisella resistance to conventional antibiotics through small molecule adjuvants}, volume={7}, ISSN={["2040-2511"]}, DOI={10.1039/c5md00353a}, abstractNote={A screen of 20 compounds identified small molecule adjuvants capable of potentiating antibiotic activity against Francisella philomiragia.}, number={1}, journal={MEDCHEMCOMM}, author={Stephens, Matthew D. and Hubble, Veroncia B. and Ernst, Robert K. and Hoek, Monique L. and Melander, Roberta J. and Cavanagh, John and Melander, Christian}, year={2016}, pages={128–131} }