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

• Published in: Chemical biology & drug design Vol. 92; no. 2; pp. 1403 - 1408
• Main Authors: Martin, Sara E., Nguyen, Catherine M., Basaraba, Randall J., Melander, Christian
• Format: Journal Article
• Language: English
• Published: HOBOKEN Wiley 01.08.2018
• Subjects: Adjuvants, Pharmaceutic; Antitubercular Agents - chemistry; Antitubercular Agents - pharmacology; beta-Lactams - pharmacology; Biochemistry & Molecular Biology; Biofilms - drug effects; chemical biology; Chemistry, Medicinal; drug design; drug discovery; Imidazoles - chemistry; Imidazoles - metabolism; Imidazoles - pharmacology; Life Sciences & Biomedicine; Microbial Sensitivity Tests; Mycobacterium smegmatis - drug effects; Mycobacterium smegmatis - physiology; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - physiology; Pharmacology & Pharmacy; Science & Technology; chemical biology; drug discovery; drug design; SMALL-MOLECULE; TUBERCULOSIS; RESISTANCE; INHIBITORS; BACTERIAL BIOFILMS
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/cbdd.13208

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. As 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. Previously, we have shown that several 2‐aminoimidazole‐containing compounds are capable of inhibiting and dispersing biofilms and potentiating select antibiotics against Mycobacterium tuberculosis and Mycobacterium smegmatis. This study focuses on alterations in the alkyl tail region of the molecule and determining how changes in this tail region alter the biofilm dispersion and potentiation activity of the compound against M. smegmatis. Studies indicate that altering the tail portion of the molecule does alter dispersion and potentiation activity in a decoupled fashion.