Abstract
Ursolic acid (UA), a pentacyclic triterpenoid acid found in many medicinal plants and aromas, is known for its antibacterial effects against multi-drug-resistant (MDR) Gram-positive bacteria, which seriously threaten human health. Unfortunately, UA water-insolubility, low bioavailability, and systemic toxicity limit the possibilities of its application in vivo. Consequently, the beneficial activities of UA observed in vitro lose their potential clinical relevance unless water-soluble, not cytotoxic UA formulations are developed. With a nano-technologic approach, we have recently prepared water-soluble UA-loaded dendrimer nanoparticles (UA-G4K NPs) non-cytotoxic on HeLa cells, with promising physicochemical properties for their clinical applications. In this work, with the aim of developing a new antibacterial agent based on UA, UA-G4K has been tested on different strains of the Enterococcus genus, including marine isolates, toward which UA-G4K has shown minimum inhibitory concentrations (MICs) very low (0.5–4.3 µM), regardless of their resistance to antibiotics. Time-kill experiments, in addition to confirming the previously reported bactericidal activity of UA against E. faecium, also established it for UA-G4K. Furthermore, cytotoxicity experiments on human keratinocytes revealed that nanomanipulation of UA significantly reduced the cytotoxicity of UA, providing UA-G4K NPs with very high LD50 (96.4 µM) and selectivity indices, which were in the range 22.4–192.8, depending on the enterococcal strain tested. Due to its physicochemical and biological properties, UA-G4K could be seriously evaluated as a novel oral-administrable therapeutic option for tackling difficult-to-treat enterococcal infections.
Highlights
For many years, antibiotics have made it possible to counteract serious bacterial infections and to perform various medical and surgical procedures in greater safety, thanks to their protection
Antibiotic resistance has become a major probin treating infections caused by many Gram-positive bacteria, including penicillin-relem in treating infections caused by many Gram-positive bacteria, including penicillinsistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus (MRSA) and S
The molecular weight (MW) of ursolic acid (UA)-G4K was calculated as described in Sections S1.3–S1.4, including Table S1 (SM), while data concerning its water solubility are reported in Section S1.5 and Figure S2 (SM)
Summary
Antibiotics have made it possible to counteract serious bacterial infections and to perform various medical and surgical procedures in greater safety, thanks to their protection. MDR pathogens of both Gram-positive and Gram-negative species cause infections against which traditional antibiotics are no longer effective and cause an increasing number of deaths in hospitals, long-term care facilities, and community settings. The surveillance of antibiotic resistance is a global public health concern [2,3,4,5,6,7,8], and the search for new antibacterial substances, which act by mechanisms other than those of existing 4.0/). Pharmaceutics 2021, 13, 1976 for new antibacterial substances, which act by mechanisms other than those of existing antibiotics, and with a low tendency to develop resistance, is at present one of the greatest antibiotics, with a low tendency to develop resistance, is at present one of the greatest challenges and for researchers [9]. Antibiotic resistance has become a major probin treating infections caused by many Gram-positive bacteria, including penicillin-relem in treating infections caused by many Gram-positive bacteria, including penicillinsistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus (MRSA) and S
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