Cyclic and Acyclic Amine Oxide Alkyl Derivatives as Potential Adjuvants in Antimicrobial Chemotherapy against Methicillin-Resistant Staphylococcus aureus with an MDR Profile

Abstract

The dramatic intensification of antimicrobial resistance occurrence in pathogenic bacteria concerns the global community. The revitalisation of inactive antibiotics is, at present, the only way to go through this health system crisis and the use of antimicrobial adjuvants is turning out the most promising approach. Due to their low toxicity, eco-friendly characteristics and antimicrobial activity, amphoteric surfactants are good candidates. This study investigated the adjuvant potentialities of commercial acyclic and newly cyclic N-oxide surfactants combined with therapeutically available antibiotics against MDR methicillin-resistant Staphylococcus aureus (MRSA). The safety profile of the new cyclic compounds, compared to commercial surfactants, was preliminarily assessed, evaluating the cytotoxicity on human peripheral mononuclear blood cells and the haemolysis in human red blood cells. The compounds show an efficacious antimicrobial activity strongly related to the length of the carbon atom chain. In drug–drug interaction assays, all surfactants act synergistically, restoring sensitivity to oxacillin in MRSA, with dodecyl acyclic and cyclic derivatives being the most effective. After evaluating the cytotoxicity and considering the antimicrobial action, the most promising compound is the L-prolinol amine-oxide C12NOX. These findings suggest that the combination of antibiotics with amphoteric surfactants is a valuable therapeutic option for topical infections sustained by multidrug-resistant S. aureus.

Fatty Acids as Aminoglycoside Antibiotic Adjuvants Against Staphylococcus aureus

“…Antibiotic adjuvants include: (1) anti-resistance drugs such as β-lactamase inhibitors pump inhibitors, membrane permeabilizers, and biofilm inhibitors; (2) antivirulence drugs, such as quorum-sensing inhibitors, toxin inhibitors, and secretion system inhibitors; (3) host-directed therapies such as innate immune system agonists and immunomodulatory peptides; and (4) other therapies such as phage, probiotic, and oral rehydration therapies ( Gill et al, 2015 ). Various synthetic and natural compounds such as prazolopyridazine derivatives ( Schaenzer et al, 2018 ), isoflavonoids ( Abreu et al, 2017 ), plant extracts ( Abreu et al, 2016 ), cationic peptides ( Geitani et al, 2019 ), cannabidiol ( Wassmann et al, 2022 ), marine bisindole alkaloid ( Campana et al, 2020 ), cinnamonitrile ( Speri et al, 2019 ), amine oxide alkyl derivatives ( Fagnani et al, 2021 ), and brominated carbazoles ( Berndsen et al, 2022 ) have been recently proposed to be used as antibiotic adjuvants against S. aureus strains.…”

Structurally Related Liposomes Containing N-Oxide Surfactants: Physicochemical Properties and Evaluation of Antimicrobial Activity in Combination with Therapeutically Available Antibiotics

“…It was also observed that the ability to inhibit microbial growth varies with the number of methylenes present in the l -prolinol derivative skeleton, in agreement with literature reports. 25 , 31 , 47 , 48 In general, the higher the lipophilicity of the surfactant, the stronger the interactions with cell structures. 31 , 49 These considerations can be simplistic.…”

“…Moreover, surfactants bearing the N -oxide moiety can prevent protein–protein interaction 23 and confer antibacterial or antioxidant properties to the aggregates, depending on their molecular scaffold. 24 , 25 …”

“…In previous investigations, we reported the biophysical and antibacterial properties of micelles formed by the investigated synthetic N -oxide-based surfactants. 24 , 25 , 29 − 31 …”

Antistaphylococcal Activities and ADME-Related Properties of Chlorinated Arylcarbamoylnaphthalenylcarbamates

“…It can only be speculated whether the different courses of dependences of bactericidal activities against S. aureus ATCC 29213/MRSA SA 3202 (MRSA3) from isolates MRSA1/MRSA2 could be due to their differences in the composition of bacterial membranes [55][56][57][58]. The effect of changing the length of the hydrocarbon tail affecting the extent of antimicrobial activity of the compounds has been discussed (e.g., [36,37,[39][40][41][42][43][44]59,60]). The decrease in biological activity at a higher chain length as a cut-off effect is discussed above.…”