Chalcones, stilbenes and ketones have anti-infective properties via inhibition of bacterial drug-efflux and consequential synergism with antimicrobial agents

Abstract

With antimicrobial resistance creating a major public health crisis, the designing of novel antimicrobial compounds that effectively combat bacterial infection is becoming increasingly critical. Interdisciplinary approaches integrate the best features of whole-cell phenotypic evaluation to validate novel therapeutic targets and discover new leads to combat antimicrobial resistance. In this project, whole-cell phenotypic evaluation such as testing inhibitors on bacterial growth, viability, efflux pump, biofilm formation and their interaction with other drugs were performed on a panel of Gram-positive, Gram-negative and acid-fast group of bacterial species. This enabled additional antimicrobial activities of compounds belonging to the flavonoid family including ketones, chalcones and stilbenes, to be identified. Flavonoids have received renewed attention in literature over the past decade, and a variety of beneficial effects of these compounds have been illuminated, including anti-cancer, anti-inflammatory, anti-tumour as well as anti-fungal and anti-bacterial. However, their mechanisms of action are yet to be identified. In this paper, we found that the compounds belonging to the flavonoid family exerted a range of anti-infective properties being identified as novel efflux pump inhibitors, whilst offering the opportunity to be used in combination therapy. The compound 2-phenylacetophenone displayed broad-spectrum efflux pump inhibition activity, whilst trans-chalcone, displayed potent activity against Gram-negative and mycobacterial efflux pumps causing inhibition higher than known potent efflux pump inhibitors, verapamil and chlorpromazine. Drug-drug interaction studies also highlighted that 2-phenylacetophenone not only has the potential to work additively with known antibacterial agents that affect the cell-wall and DNA replication but also trans-chalcone has the potential to work synergistically with anti-tubercular agents. Overall, this paper shows how whole-cell phenotypic analysis allows for the discovery of new antimicrobial agents and their consequent mode of action whilst offering the opportunity for compounds to be repurposed, in order to contribute in the fight against antimicrobial resistance.

Antioxidant, Antimicrobial, Cytotoxicity, and Larvicidal Activities of Selected Synthetic Bis-Chalcones

“…Previous studies have also indicated their bactericidal properties against various pathogenic microbial organisms [ 31 , 32 , 33 ]. Emerging studies have also indicated that chalcones and their derivatives prevent biofilm formation in bacterial colonies [ 34 , 35 , 36 ] and enhance antibiotic sensitivity [ 37 , 38 ]. The bacterial strains used are pathogenic to humans and animals as well as known to be lethal in many conditions [ 39 , 40 ].…”

Antimicrobial and Anti-Inflammatory Activity of Apple Polyphenol Phloretin on Respiratory Pathogens Associated With Chronic Obstructive Pulmonary Disease

“…Currently, the primary pharmacological intervention for treating bacterial-induced exacerbations is antibiotic therapy, which may reduce an individual’s frequency of exacerbations ( Ramos et al., 2014 ; Huckle et al., 2018 ) but overall, may increase the risk of resistant bacterial growth in patients ( Huckle et al., 2018 ). Polyphenols reduce bacterial antibiotic resistance mechanisms, such as drug efflux, and potentiate antibiotic efficacy ( Dey et al., 2015 ; Suriyanarayanan and Sarojini Santhosh, 2015 ), including compounds in the chalcone structural family in which phloretin belongs ( Ferraz et al., 2020 ; Hellewell and Bhakta, 2020 ). These results provide the basis for further studies to examine the ability of phloretin to improve bacterial-induced symptoms in COPD or to augment antibiotic therapy and potentiate its efficacy.…”

Synthesis of Dibenzalacetone using Sonochemistry and Its Antibacterial Activity Against Escherichia coli

“…ketones have demonstrated antibacterial effectiveness against a range of pathogens, including E. coli [5], Staphylococcus aureus [6], and Bacillus subtilis [7]. Notably, dibenzalacetone, a ketone compound widely utilized in cosmetic sunscreens [8], has also been identified for its antioxidant [9] and antileishmanial activities [10].…”