Quorum Sensing Inhibitors to Quench P. aeruginosa Pathogenicity

The emergence and the dissemination of multidrug-resistant bacteria constitute a major public health issue. Among incriminated Gram-negative bacteria, Pseudomonas aeruginosa has been designated by the WHO as a critical priority threat. During the infection process, this pathogen secretes various virulence factors in order to adhere and colonize host tissues. Furthermore, P. aeruginosa has the capacity to establish biofilms that reinforce its virulence and intrinsic drug resistance. The regulation of biofilm and virulence factor production of this micro-organism is controlled by a specific bacterial communication system named Quorum Sensing (QS). The development of anti-virulence agents targeting QS that could attenuate P. aeruginosa pathogenicity without affecting its growth seems to be a promising new therapeutic strategy. This could prevent the selective pressure put on bacteria by the conventional antibiotics that cause their death and promote resistant strain survival. This review describes the QS-controlled pathogenicity of P. aeruginosa and its different specific QS molecular pathways, as well as the recent advances in the development of innovative QS-quenching anti-virulence agents to fight anti-bioresistance.

New Perspectives on Old and New Therapies of Staphylococcal Skin Infections: The Role of Biofilm Targeting in Wound Healing

Among the most common complications of both chronic wound and surgical sites are staphylococcal skin infections, which slow down the wound healing process due to various virulence factors, including the ability to produce biofilms. Furthermore, staphylococcal skin infections are often caused by methicillin-resistant Staphylococcus aureus (MRSA) and become a therapeutic challenge. The aim of this narrative review is to collect the latest evidence on old and new anti-staphylococcal therapies, assessing their anti-biofilm properties and their effect on skin wound healing. We considered antibiotics, quorum sensing inhibitors, antimicrobial peptides, topical dressings, and antimicrobial photo-dynamic therapy. According to our review of the literature, targeting of biofilm is an important therapeutic choice in acute and chronic infected skin wounds both to overcome antibiotic resistance and to achieve better wound healing.

In vitro reconstituted quorum sensing pathways enable rapid evaluation of quorum sensing inhibitors

Quorum sensing, as inner- or inter-species microbial communication process orchestrated by diffusible autoinducers, typically results in collective pathogenic behaviours, being recognized as a promising druggable target for anti-virulence. Here, we reconstituted las and rhl quorum sensing pathways of Pseudomonas aeruginosa, mediated by acyl-homoserine lactones (AHLs) and LuxI/LuxR-family proteins, with fluorescence output in Escherichia coli cell-free expression system, offering a platform to rapidly evaluate quorum sensing inhibitors (QSIs) in vitro. Previously reported small-molecule quorum sensing inhibitors for interfering with P. aeruginosa quorum sensing systems were tested and showed mild to high on-target inhibition as well as off-target toxicity. Of note, quercetin displayed potent on-target inhibition to quorum sensing pathways as well as acceptable off-target toxicity to cell-free expression machinery. Upon our work, cell-free platform is anticipated to further facilitate automated and high-throughput drug screening, bridge in silico and in vivo drug-screening methods, and accelerate the upgrading of antimicrobial arsenal.

Synthesis and Reactivity of Dihalofuranones

Background: Halogenated furanones have been found to act as potent quorum sensing inhibitors in several bacterial species. It is believed that dihalofuranones covalently bind to the LuxS enzyme, which is necessary for autoinducer-2 synthesis. In addition to their antimicrobial activity, halogenated furanones also possess anti-cancer, antioxidant, and depigmentation properties. However, traditional routes to these compounds are low-yielding and capricious. Objective: This study aimed at investigating higher-yielding preparations of gem-dihalofuranones and comparing their reactivity using Suzuki chemistry. Methods: Ramirez dibromoolefination of maleic anhydride was optimised using a variety of conditions. A similar route was investigated for the preparation of bromofluorofuranones and dichlorofuranones. The conversion of a dichlorofuranone to the corresponding iodofuranone derivatives using microwave-assisted Finkelstein chemistry was also studied. Lastly, the reactivity of the different dihalofuranones was compared by Pd-mediated coupling with phenylboronic acid. Results: A higher-yielding, concise synthesis of dibromofuranones was developed using a modified Ramirez reaction. Additionally, a telescoped preparation of dichlorofuranone proved higher yielding than previous approaches. Bromine- and iodine-substituted dihalofuranones proved more reactive than their chlorine-substituted analogues. Conclusion: Higher yielding routes to bromine-, fluorine-, chlorine- and iodine-containing dihalofuranones were successfully developed. Suzuki couplings of gem-dihalofuranones were found to proceed with high stereoselectivity.