Design, synthesis, and synergistic activities of 2-aminothiazolyl compounds as potent colistin adjuvants against Acinetobacter baumannii

Abstract

Multidrug-resistant (MDR) bacteria pose a critical threat to global health, necessitating novel therapeutic strategies. The combination of the last-resort antibiotic colistin with non-antibiotic substances has been identified as a promising approach to enhance its efficacy and mitigate toxicity. Starting from a 2-aminothiazole (compound 1) identified from our in-house library, we designed and synthesized a focused series of novel benzothiazole derivatives to improve colistin potentiation. Compound C17, featuring a 3,5-bis(trifluoromethyl)phenyl moiety, emerged as the most potent hit, reducing the minimal inhibitory concentration (MIC) of colistin against Acinetobacter baumannii (A. baumannii) ATCC19606 by 66-fold, with a compelling fractional inhibitory concentration index (FICI) of 0.094. Time-kill assays confirmed that the combination of C17 and colistin resulted in synergistic and bactericidal activities, preventing the regrowth observed with colistin alone. In a murine systemic infection model, the combination therapy modestly increased the survival rate to 20% compared to the monotherapy groups. Furthermore, in silico ADMET profiling predicted good metabolic stability and oral bioavailability of C17. This work validated the 2-aminothiazole scaffold for developing colistin adjuvants and provided a promising lead compound for further optimization against A. baumannii.