title: Structural studies on 4,5-disubstituted 2-aminoimidazole-based biofilm modulators that suppress bacterial resistance to β-lactams.
abstract: 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.
authors.affiliation: Department of Chemistry, North Carolina State University, 2620 Yarborough Drive, Raleigh, NC 27695-8204 (USA).
authors.forename: Zhaoming
authors.initials: Z
authors.lastname: Su
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Yeagley
authors.forename: Rui
authors.initials: R
authors.lastname: Su
authors.forename: Lingling
authors.initials: L
authors.lastname: Peng
authors.forename: Christian
authors.initials: C
authors.lastname: Melander
mesh_terms: D000151:Acinetobacter Infections / Q000188:drug therapy / Q000382:microbiology; D040981:Acinetobacter baumannii / Q000187:drug effects* / Q000502:physiology; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000502:physiology; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000382:microbiology; D018440:beta-Lactam Resistance / Q000187:drug effects*; D047090:beta-Lactams / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D007093:Imidazoles; D047090:beta-Lactams; C014973:2-aminoimidazole