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Structural Studies on 4,5‐Disubstituted 2‐Aminoimidazole‐Based Biofilm Modulators that Suppress Bacterial Resistance to β‐Lactams
Author(s) -
Su Zhaoming,
Yeagley Andrew A.,
Su Rui,
Peng Lingling,
Melander Christian
Publication year - 2012
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201200350
Subject(s) - biofilm , microbiology and biotechnology , acinetobacter baumannii , antibiotics , staphylococcus aureus , antibiotic resistance , chemistry , methicillin resistant staphylococcus aureus , triazole , multiple drug resistance , antimicrobial , acinetobacter , bacteria , biology , genetics , organic chemistry , pseudomonas aeruginosa
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.