Analogue synthesis reveals decoupling of antibiofilm and β-lactam potentiation activities of a lead 2-aminoimidazole adjuvant against Mycobacterium smegmatis

Biofilm formation is one of the many mechanisms bacteria utilize to survive antibiotic treatment. It has been demonstrated that when Mycobacterium tuberculosis exists in a biofilm in vitro it expresses phenotypic resistance to antimicrobial drugs. Since the in vivo survival of M. tuberculosis following drug treatment is potentially linked to a biofilm-like expression of drug tolerance, it is hypothesized that biofilm dispersion should increase antibiotic susceptibility and reduce the duration of the current antibiotic treatment regimen. Previously, we have identified a 2-aminoimidazole (2-AI) compound capable of dispersing and inhibiting M. tuberculosis and M. smegmatis biofilms in vitro. Additionally, this compound potentiated the activity of carbenicillin against M. tuberculosis and, to a lesser degree, M. smegmatis. Here, we describe a SAR study on this compound evaluating each derivative for biofilm dispersion and β-lactam potentiation capabilities against M. smegmatis. This study identified a compound that improved upon the biofilm dispersion capabilities of the lead compound. Interestingly, a different compound was identified with an increased ability to potentiate a subset of β-lactam antibiotics. These compounds indicate that biofilm dispersion and potentiation capabilities may not be associated.