Organic Chemistry Seminar: Multifunctional Aminoglycoside Adjuvants

Abstract:

The world is facing an enormous threat from the emergence and dissemination of bacterial pathogens that are resistant to almost all currently available antibiotics. The problem is arguably most serious for Gram-negative bacteria (GNB) which are frequently multidrug-resistant (MDR) and for which no novel drug class has been developed in decades. Our inability to discover new GNB-active antibiotics with novel modes of action forces us to seek new approaches. One such strategy is to employ antibacterial adjuvants which are small molecules that potentiate an antibiotic against the resistant pathogen. We recently have demonstrated that aminoglycoside-based adjuvants (AGAs) can revive fluoroquinolone antibiotics and restore antibacterial efficacy against multidrug-resistant (MDR) and extremely drug-resistant (XDR) Pseudomonas aeruginosa isolates.¹ In addition, we also have demonstrated that AGAs can possess immunomodulatory properties (a) by boosting the innate immune responses and (b) by controlling the inflammatory response induced in the presence of endotoxin.² These discoveries set the stage to develop novel multifunctional AGAs for the treatment of nosocomial infections caused by P. aeruginosa.

¹ Gorityala BK, Guchhait G, Fernando DM, Deo S, McKenna SA, Zhanel GG, Kumar A, Schweizer F. Angew Chem Int Ed Engl. 2015 Nov 26. doi: 10.1002/anie.201508330

² Guchhait G, Altieri A, Gorityala B, Yang X, Findlay B, Zhanel GG, Mookherjee N, Schweizer F. Angew. Chem. Int. Ed. Engl. 2015 54, 6278-82.

Seminar Organizer: Dr. Roman Dobrovetsky