Discovery of Furanoquinone Derivatives as a Novel Class of DNA Polymerase and Gyrase Inhibitors for MRSA Eradication in Cutaneous Infection

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) is the primary microbe responsible for skin infections that are particularly difficult to eradicate. This study sought to inhibit planktonic and biofilm MRSA using furanoquinone-derived compounds containing imine moiety. A total of 19 furanoquinone analogs were designed, synthesized, and assessed for anti-MRSA potency. Among 19 compounds, (Z)-4-(hydroxyimino)naphtho[1,2- b ]furan-5(4 H )-one (HNF) and (Z)-4-(acetoxyimino)naphtho[1,2- b ]furan-5(4 H )-one (ANF) showed antibacterial activity superior to the others based on an agar diffusion assay. HNF and ANF exerted a bactericidal effect with a minimum inhibitory concentration (MIC) of 9.7 ∼ 19.5 and 2.4 ∼ 9.7 μg/ml, respectively. Both compounds were able to reduce the MRSA count by 1,000-fold in biofilm as compared to the control. In vivo efficacy was evaluated using a mouse model of skin infection. Topical application of lead compounds significantly suppressed abscess occurrence and the MRSA burden, and also ameliorated the skin-barrier function. The biochemical assay indicated the compounds’ inhibition of DNA polymerase and gyrase. In silico docking revealed a favorable interaction of the compounds with DNA polymerase and gyrase although the binding was not very strong. The total DNA analysis and proteomic data suggested a greater impairment of some proteins by HNF than ANF. In general, HNF and ANF were similarly potent in MRSA inhibition in vitro and in vivo . The findings demonstrated that there was room for structural modification of furanoquinone compounds that could be used to identify anti-MRSA agent candidates.

Design, Synthesis, and Anti-Bacterial Evaluation of Triazolyl-Pterostilbene Derivatives

“…Therefore, the development of new antimicrobial agents is very urgent and important. Modern antibacterial drug discovery is associated with a variety of targets such as DNA polymerases and topoisomerases, or those that affect cell-wall synthesis [8,9].…”

Synthetic Naphthofuranquinone Derivatives Are Effective in Eliminating Drug-Resistant Candida albicans in Hyphal, Biofilm, and Intracellular Forms: An Application for Skin-Infection Treatment

“…The protocols for synthesizing TCH-1139 and TCH-1199 were described in our previous investigation ( Tseng et al, 2010 ). The synthetic protocols for the other compounds were shown in another study ( Yang et al, 2019 ). The structures of all compounds were confirmed by 1 H NMR, 13 C NMR, and electrospray ionization mass spectrometry as exhibited previously.…”

Coenzyme Q0 From Antrodia cinnamomea Exhibits Drug-Resistant Bacteria Eradication and Keratinocyte Inflammation Mitigation to Ameliorate Infected Atopic Dermatitis in Mouse

“…The bacteria were grown and diluted to achieve an OD 600 of 0.3. MRSA were treated by CoQ 0 at 312 µg/ml for 4 h. The preparation of the samples for visualization under scanning electron microscopy (SEM) and transmission electron microscopy (TEM) was described in the previous reports (Alalaiwe et al, 2018; Yang et al, 2019).…”

“…A wrapping assay was conducted to analyze topoisomerase and gyrase. The detailed procedures of these methods were described previously (Yang et al, 2019).…”