5-Benzylidene-4-oxazolidinones potently inhibit biofilm formation in Methicillin-resistant Staphylococcus aureus

Abstract

Investigation into the biological function of 5-benzylidene-4-oxazolidinones revealed dose-dependent inhibition of biofilm formation in Methicillin-resistant S. aureus (MRSA). This structurally unusual class of small molecules inhibit up to 89% of biofilm formation with IC50 values as low as 0.78 μM, and disperse pre-formed biofilms with IC50 values as low as 4.7 μM. Together, these results suggest that 4-oxazolidinones represent new chemotypes to enable the study of bacteral biofilms with small molecule chemical probes.

Synthesis and Biological Evaluation of the Antimicrobial Natural Product Lipoxazolidinone A

“…Thesynoxazolidinone family of natural products,highlighted by synoxazolidinone A(2)is the only other class of 4-oxazolidinone natural products; albeit, they possess diminished antimicrobial activity and instead possess potent anti-biofilm activity ( Figure 1a). [12][13][14][15][16] Thes tructurally related 2-oxazolidinone antibiotics,r epresented by linezolid (3)a nd tedizolid (4), are synthetic molecules that target bacterial protein synthesis ( Figure 1b). Herein, we describe our efforts to synthesize the lipoxazolidinone family of natural products,aseries of targeted analogues and provide insights into their susceptibility to resistance and their mechanism of antimicrobial action.…”

5‐Benzylidene‐4‐Oxazolidinones Are Synergistic with Antibiotics for the Treatment of Staphylococcus aureus Biofilms

“…There have been several novel classes of small molecules that inhibit, disperse, eradicate, or modulate MRSA and other bacterial biofilms, often based on of natural product leads . Representative examples include the 2‐aminoimidazoles (2AI), meridianin D analogues, halogenated quinolines, hydroxybenzylidene‐indolinones, bromophenol‐thiohydantoins, and 2‐dichloroalkyl‐5‐benzylidene‐4‐oxazolidinones . During our initial investigation into the 2‐dichloroalkyl‐4‐oxazolidinones, and as part of our broader program to develop novel 4‐oxazolidinone antimicrobial agents, we identified potent biofilm‐inhibiting and ‐dispersing agents, and established an initial structure–activity relationship (SAR) for these synoxazolidinone natural‐product analogues (Figure A).…”

“…We next tested the biofilm‐inhibition and ‐dispersion activities of select compounds, looking to evaluate how these analogues compared with the already potent dichlorinated oxazolidinone derivatives prepared previously . Most of the alkyl derivatives tested ( 5 , 7 , 9 , 10 , 12 , 14 , 18 , 22 , and 23 ) possessed low levels of inhibition and dispersion, with none of these new analogues reaching 50 % activity at 40 μ m (Figure C).…”

5-Benzylidene-4-Oxazolidinones are Synergistic with Antibiotics for the Treatment of Staphylococcus Aureus Biofilms

“…We next tested the biofilm-inhibition and -dispersion activities of select compounds, looking to evaluate how these analogues compared with the already potent dichlorinated oxazolidinone derivatives prepared previously. [34] Most of the alkyl derivatives tested (5,7,9,10,12,14,18,22, and 23) possessed low levels of inhibition and dispersion, with none of these new analogues reaching 50 % activity at 40 mm (Figure 2 C). Importantly, 15 and 24, the two most active compounds in our MIC assays, were able to inhibit and disperse biofilms in a dose-dependent manner.…”

“…[22][23][24][25] Representative examples include the 2-aminoimidazoles (2AI), [26][27][28] meridianin D analogues, [29] halogenated quinolines, [30,31] hydroxybenzylidene-indolinones, [32] bromophenolthiohydantoins, [33] and 2-dichloroalkyl-5-benzylidene-4-oxazolidinones. [34] During our initial investigation into the 2-dichloroalkyl-4-oxazolidinones, [34] and as part of our broader program to develop novel 4-oxazolidinone antimicrobial agents, [34][35][36][37][38] we identified potent biofilm-inhibiting and -dispersing agents, and established an initial structure-activity relationship (SAR) for these synoxazolidinone natural-product analogues (Figure 1 A). Herein, we expand on the SAR of these synoxazolidinone analogues [39] and explore their ability to act in concert with common antibiotics against S. aureus biofilms (Figure 1 B).…”