A new reduced chalcone-derivative affects the membrane permeability and electric potential of multidrug-resistant Enterococcus faecalis

Author(s):Show less -

Tempone, Andre Gustavo ; dos Santos Theodoro, Reinaldo ; Romanelli, Maiara Maria ; Ferreira, Dayana Agnes Santos ; Amaral, Maiara ; de Assis, Leticia Ribeiro ; Cruz, Lucas Monteiro Santa ; Costa, Alan Roberto ; Zanella, Rosemeire Cobo ; Christodoulides, Myron ; Regasini, Luis Octavio ; Camargo, Carlos Henrique

• Document type: Journal article
• Source: Chemico-Biological Interactions; v. 365, p. 8-pg., 2022-08-10.

Abstract

The emergence and spread of multidrug-resistant (MDR) enterococci and other Gram-positive bacteria represents a severe problem due to the lack of effective therapeutic alternatives. Natural products have long been an important source of new antibacterial scaffolds and can play a key role in the current antibiotic crisis. Entero-cocci are predominantly non-pathogenic gastrointestinal commensal bacteria, but among them, Enterococcus faecalis and Enterococcus faecium represent the species that account for most clinically relevant infections. The emergence of MDR enterococci has reduced the available antibiotic treatment options and highlights the need to develop new antimicrobial compounds. In the search for new hit compounds against MDR Enterococcus spp., natural-derived compounds represent inspiring scaffolds for drug design studies. In this work, the antimicrobial activity of a fully synthetic chalcone derivative (r4MB) was determined on a clinical panel of 34 MDR Gram-positive bacteria, mostly constituted by E. faecalis and E. faecium, along with Staphylococcus spp., amongst others. Compound r4MB showed activity against 100% of the tested strains, with the minimum inhibitory concentration (MIC) in the range of 5-20 mu M. The lethal action of the compound was evaluated using different fluorescent-based assays. The compound showed a time-dependent permeabilisation of the membrane of a vancomycin-resistant E. faecalis, detected by the fluorescent probe SYTOX Green, and digital fluorescent mi-croscopy corroborated the spectrofluorimetric analysis within 6 min of incubation. Flow cytometry analysis of the membrane electric potential demonstrated a significant depolarization, confirming the target of the com-pound towards the bacterial membrane. No cytotoxic haemolysis was observed with mammalian erythrocytes, and a 99% cytotoxic concentration of 118 mu M on NCTC cells demonstrated a promising antimicrobial selectivity. In silico studies using SwissADME and ADMETLabs servers suggest that compound r4MB displayed adequate ADME properties, with no alerts for pan-assay interference compounds (PAINS). Future hit-to-lead optimization of this chalcone derivative can contribute to developing a more potent derivative against infections caused by MDR enterococci. (AU)

• FAPESP's process: 14/18330-0 - Synthesis and biological evaluation of curcumin-cinnamaldehyde hybrids as bacterial cell division inhibitors
• Grantee: Luis Octávio Regasini
• Support Opportunities: Regular Research Grants
• FAPESP's process: 21/04464-8 - Microbial and plant prototypes as drug candidates for protozoan neglected diseases and multidrug-resistant bacteria
• Grantee: André Gustavo Tempone Cardoso
• Support Opportunities: Regular Research Grants
• FAPESP's process: 18/26655-7 - Natural metabolites for treating antimicrobial resistant gonorrhoea and visceral leishmaniasis
• Grantee: André Gustavo Tempone Cardoso
• Support Opportunities: Regular Research Grants
• FAPESP's process: 19/11979-4 - Synthesis and evaluation of 4-Hydroxyderricini (4-HD) and its analogs as potential agents against tuberculosis
• Grantee: Reinaldo dos Santos Theodoro
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 17/50333-7 - Institutional research development plan of the Instituto Adolfo Lutz (PDIp)
• Grantee: Carlos Henrique Camargo
• Support Opportunities: Research Grants - State Research Institutes Modernization Program
• FAPESP's process: 18/15083-2 - Synthesis and biological evaluation of isobavachalcone (IBC) and analogs as potential agents against tuberculosis
• Grantee: Luis Octávio Regasini
• Support Opportunities: Regular Research Grants
• FAPESP's process: 09/53989-4 - Acquisition of a nuclear magnetic resonance spectrometer for studies of biomolecules
• Grantee: Raghuvir Krishnaswamy Arni
• Support Opportunities: Multi-user Equipment Program