ABSTRACT
The objective of this study is to take the initial steps toward developing novel antibiotics to counteract the escalating problem of antimicrobial and bacterial persistence, particularly in relation to biofilms. Our approach involves emulating the structural characteristics of cationic antimicrobial peptides. To circumvent resistance development, we have designed a library of bis-benzimidazolium salts that selectively target the microbial membranes in a nonspecific manner. To explore their structure-activity relationship, we conducted experiments using these compounds on various pathogens known for their resistance to conventional antibiotics, including Gram-positive methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecium (VRE), and Gram-negative Escherichia coli (E. coli). Notably, two bis-benzimidazolium salts exhibited robust antimicrobial activity while maintaining a high level of selectivity compared with mammalian cells. Our investigations revealed significant antibiofilm activity, as these compounds rapidly acted against established biofilms. In addition, bis-benzimidazolium compounds exhibited consistent results in resistance development and cross-resistance studies. Consequently, amphiphilic bis-benzimidazolium salts hold promise as potential candidates to combat resistance-associated infections.
Subject(s)
Anti-Infective Agents , Bacterial Infections , Methicillin-Resistant Staphylococcus aureus , Animals , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Salts , Escherichia coli , Drug Resistance, Bacterial , Anti-Infective Agents/pharmacology , Biofilms , MammalsABSTRACT
We present the development of surfactant-free, silica-free and fully biobased oil-in-water antimicrobial Pickering emulsions, based on the self-assembly of ß-cyclodextrin and phytoantimicrobial oils (terpinen-4-ol or carvacrol). Undecylenic acid (UA), derived from castor oil, can be used as bio-based drug to treat fungal infection, but is less effective than petroleum-based drugs as azole derivatives. To maximize its antifungal potential, we have incorporated UA in fully biobased Pickering emulsions. These emulsions are effective against fungi, Gram-positive and Gram-negative bacteria. The carvacrol emulsion charged with UA is +390 % and +165 % more potent against methicillin-resistant S. aureus (MRSA), compared to UA and azole-based commercial formulations. Moreover, this emulsion is up to +480 % more efficient that UA ointment against C. albicans. Finally, remarkable eradication of E. coli and MRSA biofilms was obtained with this environmental-friendly emulsion.
Subject(s)
Anti-Bacterial Agents/pharmacology , Antifungal Agents/pharmacology , Cymenes/pharmacology , Undecylenic Acids/pharmacology , beta-Cyclodextrins/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Antifungal Agents/chemical synthesis , Antifungal Agents/chemistry , Candida albicans/drug effects , Castor Oil/chemistry , Cymenes/chemical synthesis , Cymenes/chemistry , Dose-Response Relationship, Drug , Emulsions/chemical synthesis , Emulsions/chemistry , Emulsions/pharmacology , Escherichia coli/drug effects , Methicillin-Resistant Staphylococcus aureus/drug effects , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity Relationship , Undecylenic Acids/chemical synthesis , Undecylenic Acids/chemistry , beta-Cyclodextrins/chemical synthesis , beta-Cyclodextrins/chemistryABSTRACT
We present self-assembled Pickering emulsions containing biocidal phytochemical oils (carvacrol and terpinen-4-ol) and ß-cyclodextrin able to potentiate the antimicrobial and antibiofilm activity of miconazoctylium bromide. The carvacrol-containing emulsion is 2-fold more sensitive against C. albicans and S. aureus and highly active against E. coli, compared to the commercial cream containing miconazole nitrate. Moreover, this emulsion shows a synergistic effect against fungi, additive responses against bacteria, and remarkable staphylococcal biofilm eradication. These results are associated with membrane permeabilization, enzymes inhibition, and the accumulation of reactive oxygen species in microorganisms.
Subject(s)
Anti-Bacterial Agents/pharmacology , Antifungal Agents/pharmacology , Biofilms/drug effects , Cyclodextrins/chemistry , Emulsions/chemistry , Candida albicans/drug effects , Cymenes/pharmacology , Escherichia coli/drug effects , Methicillin-Resistant Staphylococcus aureus/drug effects , Methicillin-Resistant Staphylococcus aureus/physiology , Terpenes/pharmacologyABSTRACT
Emergence of resistant bacteria encourages us to develop new antibiotics and strategies to compensate for the different mechanisms of resistance they acquire. One of the defense mechanisms of resistant bacteria is the formation of biofilms. Herein we show that benzimidazolium salts with various flexible or rigid side chains act as strong antibiotic and antibiofilm agents. We show that their antibiofilm activity is due to their capacity to destroy the biofilm matrix and the bacterial cellular membranes. These compounds are able to avoid the formation of biofilms and disperse mature biofilms showing a universal use in the treatment of biofilm-associated infections.
ABSTRACT
The increased prevalence of antibiotic-resistant bacteria is a critical issue for human health. Developing new antibiotic agents is vital for fighting persistent infections and lowering mortality rates. In this study, we designed lutidine-disubstituted bis-benzimidazolium salts (lutidine-bis-benzimidazolium core with octyl, adamantyl, and cholesteryl lipophilic side chains), and tested their antimicrobial activity, their capacity to inhibit planktonic bacterial and fungal growth, and their ability to inhibit the formation of or disrupt mature methicillin-resistant Staphylococcus aureus (MRSA) biofilms. The antibiofilm activity of these salts was analyzed in terms of their lipophilicity, capacity to induce transmembrane ion transport, perturbation of the cellular membrane, and mechanism of action in the phospholipid bilayer. The synthesized compounds were not active against MRSA biofilms, as the formation of transmembrane channels had no effect on the integrity of the extracellular polymeric substance matrix and only octyl and adamantyl derivatives possessed the capacity to inhibit biofilm formation. The synthesized derivatives could be used as lead candidates for the development of anti-MRSA agents.
Subject(s)
Anti-Infective Agents/chemistry , Anti-Infective Agents/pharmacology , Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Biofilms/drug effects , Methicillin-Resistant Staphylococcus aureus/drug effects , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Bacillus thuringiensis/drug effects , Bacillus thuringiensis/physiology , Bacterial Infections/drug therapy , Bacterial Infections/microbiology , Biofilms/growth & development , Candida/drug effects , Candidiasis/drug therapy , Drug Design , Escherichia coli/drug effects , Escherichia coli/physiology , Humans , Methicillin-Resistant Staphylococcus aureus/physiology , Microbial Sensitivity Tests , Models, Molecular , Salts/chemistry , Salts/pharmacology , Staphylococcal Infections/drug therapy , Staphylococcal Infections/microbiologyABSTRACT
We designed and synthesized miconazole analogues containing a substituted imidazolium moiety. The structural modification of the miconazole led to a compound with high potency to prevent the formation and disrupt bacterial biofilms, as a result of accumulation in the biofilm matrix, permeabilization of the bacterial membrane and generation of reactive oxygen species in the cytoplasm.
Subject(s)
Anti-Bacterial Agents/pharmacology , Biofilms/drug effects , Methicillin-Resistant Staphylococcus aureus/drug effects , Miconazole/analogs & derivatives , Miconazole/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/toxicity , Hemolysis/drug effects , Humans , Miconazole/chemical synthesis , Miconazole/toxicity , Microbial Sensitivity TestsABSTRACT
Constrained analogs containing a 2-hydroxymethylpyrrolidine core of the natural sphingolipids sphingosine, sphinganine, N,N-dimethylsphingosine and N-acetyl variants of sphingosine and sphinganine (C2-ceramide and dihydro-C2-ceramide) were synthesized and evaluated for their ability to down-regulate nutrient transporter proteins and trigger cytoplasmic vacuolation in mammalian cells. In cancer cells, the disruptions in intracellular trafficking produced by these sphingolipids lead to cancer cell death by starvation. Structure activity studies were conducted by varying the length of the hydrocarbon chain, the degree of unsaturation and the presence or absence of an aryl moiety on the appended chains, and stereochemistry at two stereogenic centers. In general, cytotoxicity was positively correlated with nutrient transporter down-regulation and vacuolation. This study was intended to identify structural and functional features in lead compounds that best contribute to potency, and to develop chemical biology tools that could be used to isolate the different protein targets responsible for nutrient transporter loss and cytoplasmic vacuolation. A molecule that produces maximal vacuolation and transporter loss is expected to have the maximal anti-cancer activity and would be a lead compound.