A New Kind of Quinonic-Antibiotic Useful Against Multidrug-Resistant S. aureus and E. faecium Infections.

Javier Campanini-Salinas,Pedro Alarcón,Gonzalo Recabarren Gajardo,Duane Choquesillo-Lazarte,Mario Faúndez,David Vásquez-Velásquez,Roberto Vidal,Francisco Silva,Marcelo Kogan,Juan Andrades-Lagos,Gerardo Gonzalez Rocha,Jaime Mella,Soledad Bollo Dragnic,Edison Salas-Huenuleo

doi:10.3390/molecules23071776

Abstract

A rapid emergence of resistant bacteria is occurring worldwide, endangering the efficacy of antibiotics and reducing the therapeutic arsenal available for treatment of infectious diseases. In the present study, we developed a new class of compounds with antibacterial activity obtained by a simple, two step synthesis and screened the products for in vitro antibacterial activity against ATCC® strains using the broth microdilution method. The compounds exhibited minimum inhibitory concentrations (MIC) of 1–32 μg/mL against Gram-positive ATCC® strains. The structure–activity relationship indicated that the thiophenol ring is essential for antibacterial activity and the substituents on the thiophenol ring module, for antibacterial activity. The most promising compounds detected by screening were tested against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VREF) clinical isolates. We found remarkable activity against VREF for compounds 7 and 16, were the MIC50/90 were 2/4 µg/mL and 4/4 µg/mL, respectively, while for vancomycin the MIC50/90 was 256/512 µg/mL. Neither compound affected cell viability in any of the mammalian cell lines at any of the concentrations tested. These in vitro data show that compounds 7 and 16 have an interesting potential to be developed as new antibacterial drugs against infections caused by VREF.

Highlights

Infectious diseases are a leading cause of death worldwide, and the increasing emergence of antibacterial resistance has contributed to rising rates of potentially fatal infections
Compounds 2–17 were obtained by nucleophilic addition of the corresponding thiophenol derivatives to core 1 with subsequent aerobic oxidation of the hydroquinone formed by Michael addition (Figure 1)
To assess the clinical potential of the most promising compounds, we evaluated their antibacterial activity against heterogeneous populations of clinical isolates as well as their toxicity against human and animal cells

Summary

Introduction

Infectious diseases are a leading cause of death worldwide, and the increasing emergence of antibacterial resistance has contributed to rising rates of potentially fatal infections. It is estimated that by 2050, diseases caused by antibiotic-resistant microorganisms will be responsible for 10 million deaths per year [1]. The bacteria implicated in these infections include the so-called ESKAPE pathogens, such as Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and various Enterobacter sp. In the United States (US), these resistant strains are responsible for over 11,000 deaths per year [5]. In the United Kingdom [6] and the US [7], up to 25% and 60% of E. faecium strains are resistant to vancomycin (VAN), respectively

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Conclusion