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.
One strategy to confront the antibiotic resistance crisis is through the development of adjuvant compounds that increase the efficacy of established drugs. A key step in the development of a natural product adjuvant as a drug is identifying the resistance process it undermines to enhance antibiotic activity.
Antibiotic resistance has significantly increased since the beginning of the 21st century. Currently, the polymyxin colistin is typically viewed as the antibiotic of last resort for the treatment of multidrug resistant Gram-negative bacterial infections. However, increased colistin usage has resulted in colistin-resistant bacterial isolates becoming more common. The recent dissemination of plasmid-borne colistin resistance genes (mcr 1−8) into the human pathogen pool is further threatening to render colistin therapy ineffective. New methods to combat antibiotic resistant pathogens are needed. Herein, the utilization of a colistin-adjuvant combination that is effective against colistin-resistant bacteria is described. At 5 μM, the lead adjuvant, which is nontoxic to the bacteria alone, increases colistin efficacy 32-fold against bacteria containing the mcr-1 gene and effects a 1024-fold increase in colistin efficacy against bacteria harboring chromosomally encoded colistin resistance determinants; these combinations lower the colistin minimum inhibitory concentration (MIC) to or below clinical breakpoint levels (≤2 μg/ mL).
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 16fold, 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.
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