Novel 2-aminothiazole analogues both as polymyxin E synergist and antimicrobial agent against multidrug-resistant Gram-positive bacteria.

The widespread emergence of antibiotic resistance poses a substantial challenge to global health. While polymyxin E serves as a final option in treatment, its effectiveness is hindered by dose-related toxicity. A crucial strategy for addressing this issue involves incorporating an antibiotic adjuvant to enhance the antibiotic's efficacy and decrease the required dosage. Here, we reported a multifunctional antibacterial compound A33, containing a 2-aminothiazole scaffold. In vitro studies demonstrated that A33 in combination with polymyxin E inhibited the growth of various Gram-negative bacteria, meanwhile with minimum inhibitory concentrations (MICs) of 0.5-4 μg/mL against twenty-three Gram-positive bacteria, including two drug-resistant strains. In vivo studies showed significant efficacy of the combined treatment of A33 and polymyxin E in a mouse infection model. The mice treated with compound A33 (64 mg/kg) and polymyxin E (0.5 mg/kg) in combination had a 100 % survival rate. Mechanistic studies suggested that A33 might exert its synergistic effect by targeting the outer membrane of Gram-negative bacteria. The ADMET data demonstrated that A33 possessed good pharmacokinetic profiles and drug-likeness properties. Overall, the optimized compound A33 assisted polymyxin E in combating various Gram-negative bacteria and exhibited bactericidal effects against drug-resistant Gram-positive bacteria, offering a new potential therapeutic approach for managing mixed bacterial infections.