Since the discovery of antimicrobial agents, the misuse of antibiotics has led to the emergence of bacterial strains resistant to both antibiotics and common disinfectants like quaternary ammonium compounds (QACs). A new class, 'gemini' QACs, which contain two polar heads, has shown promise. Octenidine (OCT), a representative of this group, is effective against resistant microorganisms but has limitations such as low solubility and high cytotoxicity. In this study, we developed 16 novel OCT derivatives. These compounds were subjected to in silico screening to predict their membrane permeation. Testing against nosocomial bacterial strains (G+ and G-) and their biofilms revealed that most compounds were highly effective against G+ bacteria, while compounds 7, 8, and 10-12 were effective against G- bacteria. Notably, compounds 6-8 were significantly more effective than OCT and BAC standards across the bacterial panel. Compound 12 stood out due to its low cytotoxicity and broad-spectrum antimicrobial activity, comparable to OCT. It also demonstrated impressive antifungal activity. Compound 1 was highly selective to fungi and four times more effective than OCT without its cytotoxicity. Several compounds, including 4, 6, 8, 9, 10, and 12, showed strong virucidal activity against murine cytomegalovirus and herpes simplex virus 1. In conclusion, these gemini QACs, especially compound 12, offer a promising alternative to current disinfectants, addressing emerging resistances with their enhanced antimicrobial, antifungal, and virucidal properties.
- MeSH
- antibakteriální látky * farmakologie chemická syntéza chemie MeSH
- antifungální látky farmakologie chemická syntéza chemie MeSH
- antivirové látky farmakologie chemická syntéza chemie MeSH
- Bacteria účinky léků MeSH
- biofilmy účinky léků MeSH
- houby účinky léků MeSH
- iminy MeSH
- kvartérní amoniové sloučeniny * farmakologie chemická syntéza chemie MeSH
- lidé MeSH
- mikrobiální testy citlivosti * MeSH
- molekulární struktura MeSH
- myši MeSH
- pyridinové sloučeniny farmakologie chemická syntéza chemie MeSH
- pyridiny farmakologie chemie chemická syntéza MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Phenotypic screening of an in-house library of small molecule purine derivatives against Mycobacterium tuberculosis (Mtb) led to the identification of 2-morpholino-7-(naphthalen-2-ylmethyl)-1,7-dihydro-6H-purin-6-one 10 as a potent antimycobacterial agent with MIC99 of 4 μM. Thorough structure-activity relationship studies revealed the importance of 7-(naphthalen-2-ylmethyl) substitution for antimycobacterial activity, yet opened the possibility of structural modifications at positions 2 and 6 of the purine core. As the result, optimized analogues with 6-amino or ethylamino substitution 56 and 64, respectively, were developed. These compounds showed strong in vitro antimycobacterial activity with MIC of 1 μM against Mtb H37Rv and against several clinically isolated drug-resistant strains, had limited toxicity to mammalian cell lines, medium clearance with respect to phase I metabolic deactivation (27 and 16.8 μL/min/mg), sufficient aqueous solubility (>90 μM) and high plasma stability. Interestingly, investigated purines, including compounds 56 and 64, lacked activity against a panel of Gram-negative and Gram-positive bacterial strains, indicating a specific mycobacterial molecular target. To investigate the mechanism of action, Mtb mutants resistant to hit compound 10 were isolated and their genomes were sequenced. Mutations were found in dprE1 (Rv3790), which encodes decaprenylphosphoryl-β-d-ribose oxidase DprE1, enzyme essential for the biosynthesis of arabinose, a vital component of the mycobacterial cell wall. Inhibition of DprE1 by 2,6-disubstituted 7-(naphthalen-2-ylmethyl)-7H-purines was proved using radiolabelling experiments in Mtb H37Rv in vitro. Finally, structure-binding relationships between selected purines and DprE1 using molecular modeling studies in tandem with molecular dynamic simulations revealed the key structural features for effective drug-target interaction.
- MeSH
- alkoholoxidoreduktasy chemie MeSH
- antituberkulotika * chemie MeSH
- bakteriální proteiny metabolismus MeSH
- Mycobacterium tuberculosis * MeSH
- puriny farmakologie MeSH
- savci metabolismus MeSH
- simulace molekulární dynamiky MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Streptococcus mutans is one of the bacteria that initiates the colonization of the pellicle at the tooth surface. It forms a plaque, together with other bacteria, which gradually dissolves the pellicle and leaves the tooth surface unprotected against the acidic oral environment. Calcium phosphate ceramics are excellent synthetic materials for the study of biofilm formation in dentistry because they are comparable to teeth in chemical composition and structure. Calcium phosphates can be processed to achieve a variety of crystalline compounds with biologically relevant ionic substitutions and structures that allow study of the effect of the surface chemistry and the topography independently. In this article, we describe the preparation and characterization of three types of calcium phosphate-based materials as a suitable surface for the formation of the S. mutans biofilm: beta-tricalcium phosphate (β-TCP); sintered hydroxyapatite (SHA); and calcium-deficient hydroxyapatite (CDHA). The densest biofilms were formed on the surfaces of SHA and CDHA, with no significant differences due to the stoichiometry or microstructure. In contrast, β-TCP showed a lower susceptibility to S. mutans biofilm formation, suggesting that the crystalline structure is the controlling parameter. Subsequently, SHA was selected to develop a dental biofilm model that allowed study of S. mutans biofilm susceptibility to chlorhexidine and ethanol.
Biofilms that grow on implant surfaces pose a great risk and challenge for the dental implant survival. In this work, we have applied Er:YAG photoacoustic irrigation using super short pulses (Er:YAG-SSP) to remove biofilms from the titanium surfaces in the non-contact mode. Mature Enterococcus faecalis biofilms were treated with saline solution, chlorhexidine, and hydrogen peroxide, or photoacoustically with Er:YAG-SSP for 10 or 60 s. The number of total and viable bacteria as well as biofilm surface coverage was determined prior and after different treatments. Er:YAG-SSP photoacoustic treatment significantly increases the biofilm removal rate compared to saline or chemically treated biofilms. Up to 92% of biofilm-covered surface can be cleaned in non-contact mode during 10 s without the use of abrasives or chemicals. In addition, Er:YAG-SSP photoacoustic irrigation significantly decreases the number of viable bacteria that remained on the titanium surface. Within the limitations of the present in vitro model, the ER:YAG-SSP seems to constitute an efficient therapeutic option for quick debridement and decontamination of titanium implants without using abrasives or chemicals.
Benzoxonium chloride belongs to the group of quaternary ammonium salts, which have been widely used for decades as disinfectants because of their high efficacy, low toxicity, and thermal stability. In this study, we have prepared the C10-C18 set of benzoxonium-like salts to evaluate the effect of their chemical and biological decontamination capabilities. In particular, biocidal activity against a panel of bacterial strains including Staphylococcus aureus in biofilm form was screened. In addition, the most promising compounds were successfully tested against Francisella tularensis as a representative of potential biological warfare agents. From a point of view of chemical warfare protection, the efficiency of BOC-like compounds to degrade the organophosphate simulant fenitrothion was examined. Notwithstanding that no single compound with universal effectiveness was identified, a mixture of only two compounds from this group would be able to satisfactorily cover the proposed decontamination spectrum. In addition, the compounds were evaluated for their cytotoxicity as a basic safety parameter for potential use in practice. In summary, the dual effect on chemical and biological agents of benzoxonium-like salts offer attractive potential as active components of decontamination mixtures in the case of a terrorist threat or chemical or biological accidents.
- Publikační typ
- časopisecké články MeSH
An increasing microbial resistance to known antibiotics raises a demand for new antimicrobials. In this study the antimicrobial properties of a series of new N-Alkylpyridinium quaternary ammonium compounds (QACs) with varying alkyl chain lengths were evaluated for several nosocomial pathogens. The chemical identities of the new QACs were determined by NMR, LC-MS, and HRMS. All the planktonic bacteria tested were susceptible to the new QACs as evaluated by MIC and MBC assays. The antimicrobial effect was most pronounced against Staphylococcus aureus clinical isolates. Live/dead staining CLSM was used to test the effectiveness of the QACs in biofilms. The effectiveness was up to 10-fold lower than in the plankton. When QACs were used as irrigants in Er:YAG - SSP photoacoustic steaming, their effectiveness significantly increased. The combined use of irrigants and photoacoustic streaming increased biofilm removal from the surface and increased the killing rate of the cells remaining on the surface. This may allow for a shorter chemical exposure time and lower dosage of QACs used in applications. The results demonstrate that the new QACs have potential to be applied as antibacterial compounds effective against planktonic and biofilm bacteria as well as irrigants in removal of difficult-to-reach biofilms.
- Publikační typ
- časopisecké články MeSH
Growing evidence of antibiotic-resistant pathogens is a serious medical issue that has to be addressed. Our antimicrobial research is focused on searching for novel small molecules that differ from the most clinically used antibiotics by chemical structure and mechanism. However, this fundamental research is like looking for a needle in a haystack. In addition, in vitro methods are time-consuming and expensive to screen large number of compounds in reasonable time. Off-target screening can represent a solution to find novel and effective antimicrobial agents that can eliminate these problems. Accordingly, molecular docking in the family of selected frentizole derivatives predicted their potential to inhibit bacterial nicotinate mononucleotide adenylyltransferase (NadD). This bacterial-essential specific enzyme has an important role in NAD metabolism. Thus, underlying mechanism of antimicrobials derived from frentizole would be interference with this biochemical process. Unfortunately, broth microdilution assay did not display any antimicrobial activity of tested compounds. On the other hand, herein we propose that off-target screening can facilitate searching for new drugs and that NadD could be a relevant target for antimicrobials.
- MeSH
- antiinfekční látky * chemie MeSH
- Bacteria MeSH
- benzothiazoly chemie MeSH
- indikátorové diluční techniky MeSH
- inhibitory enzymů chemie MeSH
- lidé MeSH
- nikotinamidnukleotidadenylyltransferasa * antagonisté a inhibitory MeSH
- simulace molekulového dockingu MeSH
- techniky in vitro MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
