Structural studies on 4,5-disubstituted 2-aminoimidazole-based biofilm modulators that suppress bacterial resistance to β-lactams.

A library of 4,5-disubstituted 2-aminoimidazole triazole amide (2-AITA) conjugates has been successfully assembled. Upon biological screening, this class of small molecules was discovered as enhanced biofilm regulators through non-microbicidal mechanisms against methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Acinetobacter baumannii (MDRAB), with active concentrations in the low micromolar range. The library was also subjected to synergism and resensitization studies with β-lactam antibiotics against MRSA. Lead compounds were identified that suppress the antibiotic resistance of MRSA by working synergistically with oxacillin, a β-lactam antibiotic resistant to penicillinase. A further structure-activity relationship (SAR) study on the parent 2-AITA compound delivered a 2-aminoimidazole diamide (2-AIDA) conjugate with significantly increased synergistic activity with oxacillin against MRSA, decreasing the MIC value of the β-lactam antibiotic by 64-fold. Increased anti-biofilm activity did not necessarily lead to increased suppression of antibiotic resistance, which indicates that biofilm inhibition and resensitization are most likely occurring via distinct mechanisms.