Yeasts such as Candida albicans, albeit being ubiquitous members of the skin, oral and vaginal mi... more Yeasts such as Candida albicans, albeit being ubiquitous members of the skin, oral and vaginal microbiome, can cause superficial to life‐threatening infections. Human cathelicidin LL‐37‐based peptides have antibacterial activity and yet, their antifungal activity remains to be thoroughly characterized. The aim of this study was to comprehensively investigate the activity of LL‐37‐based peptides against C. albicans. LL‐37 and its derivatives were tested for their ability to kill C. albicans planktonic cells in the presence of various biological matrices (serum, plasma, saliva and urine), that have been reported to inactivate peptides. The antibiofilm activity, resistance development and biocompatibility were investigated for the lead peptide. GK‐17, a 17 amino acid peptide, showed remarkable stability to fungal aspartyl proteases and rapidly killed planktonic C. albicans despite the presence of biological matrices. GK‐17 also inhibited adhesion to biotic and abiotic substrates, inhib...
Yeasts such as Candida albicans, albeit being ubiquitous members of the skin, oral and vaginal mi... more Yeasts such as Candida albicans, albeit being ubiquitous members of the skin, oral and vaginal microbiome, can cause superficial to life‐threatening infections. Human cathelicidin LL‐37‐based peptides have antibacterial activity and yet, their antifungal activity remains to be thoroughly characterized. The aim of this study was to comprehensively investigate the activity of LL‐37‐based peptides against C. albicans. LL‐37 and its derivatives were tested for their ability to kill C. albicans planktonic cells in the presence of various biological matrices (serum, plasma, saliva and urine), that have been reported to inactivate peptides. The antibiofilm activity, resistance development and biocompatibility were investigated for the lead peptide. GK‐17, a 17 amino acid peptide, showed remarkable stability to fungal aspartyl proteases and rapidly killed planktonic C. albicans despite the presence of biological matrices. GK‐17 also inhibited adhesion to biotic and abiotic substrates, inhibited biofilm formation and eradicated preformed biofilms in the presence of biological matrices. Compared to nystatin, GK‐17 had a lower propensity to allow for resistance development by C. albicans. The peptide showed concentration‐dependent biocompatibility to red blood cells, with only 30% hemolysis even at 4× the fungicidal concentration. Taken together, GK‐17 is a novel antifungal peptide with promising effects against C. albicans.
Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin intermediate-resistant Staphylo... more Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin intermediate-resistant Staphylococcus aureus (VRSA) is one among the WHO high priority pathogens. Among these two, MRSA is the most globally documented pathogen that necessitates the pressing demand for new classes of anti-MRSA drugs. Bacterial gyrase targeted therapeutics are unique strategies to overcome cross-resistance as they are present only in bacteria and absent in higher eukaryotes. The GyrB subunit is essential for the catalytic functions of the bacterial enzyme DNA Gyrase, thereby constituting a promising druggable target. The current study performed a structure-based virtual screening to designing GyrB target-specific candidate molecules. The de novo ligand design of novel hit molecules was performed using a rhodanine scaffold. Through a systematic in silico screening process, the hit molecules were screened for their synthetic accessibility, drug likeliness and pharmacokinetics properties in addition to i...
Abstract Despite the substantial research advancements on oral diseases, dental caries remains a ... more Abstract Despite the substantial research advancements on oral diseases, dental caries remains a major healthcare burden. A disease of microbial dysbiosis, dental caries is characterised by the formation of biofilms that assist demineralisation and destruction of the dental hard tissues. While it is well understood that this is a multi-kingdom biofilm-mediated disease, it has been elucidated that acid producing and acid tolerant bacteria play pioneering roles in the process. Specifically, Streptococcus mutans houses major virulence pathways that enable it to thrive in the oral cavity and cause caries. This pathogen adheres to the tooth substrate, forms biofilms, resists external stress, produces acids, kills closely related species, and survives the acid as well as the host clearance mechanisms. For an organism to be able to confer such virulence, it requires a large and complex gene network which synergise to establish disease. In this review, we have charted how these multi-faceted genes control several caries-related functions of Streptococcus mutans. In a futuristic thinking approach, we also briefly discuss the potential roles of omics and machine learning, to ease the study of non-functional genes that may play a major role and enable the integration of experimental data.
Yeasts such as Candida albicans, albeit being ubiquitous members of the skin, oral and vaginal mi... more Yeasts such as Candida albicans, albeit being ubiquitous members of the skin, oral and vaginal microbiome, can cause superficial to life‐threatening infections. Human cathelicidin LL‐37‐based peptides have antibacterial activity and yet, their antifungal activity remains to be thoroughly characterized. The aim of this study was to comprehensively investigate the activity of LL‐37‐based peptides against C. albicans. LL‐37 and its derivatives were tested for their ability to kill C. albicans planktonic cells in the presence of various biological matrices (serum, plasma, saliva and urine), that have been reported to inactivate peptides. The antibiofilm activity, resistance development and biocompatibility were investigated for the lead peptide. GK‐17, a 17 amino acid peptide, showed remarkable stability to fungal aspartyl proteases and rapidly killed planktonic C. albicans despite the presence of biological matrices. GK‐17 also inhibited adhesion to biotic and abiotic substrates, inhib...
Yeasts such as Candida albicans, albeit being ubiquitous members of the skin, oral and vaginal mi... more Yeasts such as Candida albicans, albeit being ubiquitous members of the skin, oral and vaginal microbiome, can cause superficial to life‐threatening infections. Human cathelicidin LL‐37‐based peptides have antibacterial activity and yet, their antifungal activity remains to be thoroughly characterized. The aim of this study was to comprehensively investigate the activity of LL‐37‐based peptides against C. albicans. LL‐37 and its derivatives were tested for their ability to kill C. albicans planktonic cells in the presence of various biological matrices (serum, plasma, saliva and urine), that have been reported to inactivate peptides. The antibiofilm activity, resistance development and biocompatibility were investigated for the lead peptide. GK‐17, a 17 amino acid peptide, showed remarkable stability to fungal aspartyl proteases and rapidly killed planktonic C. albicans despite the presence of biological matrices. GK‐17 also inhibited adhesion to biotic and abiotic substrates, inhibited biofilm formation and eradicated preformed biofilms in the presence of biological matrices. Compared to nystatin, GK‐17 had a lower propensity to allow for resistance development by C. albicans. The peptide showed concentration‐dependent biocompatibility to red blood cells, with only 30% hemolysis even at 4× the fungicidal concentration. Taken together, GK‐17 is a novel antifungal peptide with promising effects against C. albicans.
Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin intermediate-resistant Staphylo... more Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin intermediate-resistant Staphylococcus aureus (VRSA) is one among the WHO high priority pathogens. Among these two, MRSA is the most globally documented pathogen that necessitates the pressing demand for new classes of anti-MRSA drugs. Bacterial gyrase targeted therapeutics are unique strategies to overcome cross-resistance as they are present only in bacteria and absent in higher eukaryotes. The GyrB subunit is essential for the catalytic functions of the bacterial enzyme DNA Gyrase, thereby constituting a promising druggable target. The current study performed a structure-based virtual screening to designing GyrB target-specific candidate molecules. The de novo ligand design of novel hit molecules was performed using a rhodanine scaffold. Through a systematic in silico screening process, the hit molecules were screened for their synthetic accessibility, drug likeliness and pharmacokinetics properties in addition to i...
Abstract Despite the substantial research advancements on oral diseases, dental caries remains a ... more Abstract Despite the substantial research advancements on oral diseases, dental caries remains a major healthcare burden. A disease of microbial dysbiosis, dental caries is characterised by the formation of biofilms that assist demineralisation and destruction of the dental hard tissues. While it is well understood that this is a multi-kingdom biofilm-mediated disease, it has been elucidated that acid producing and acid tolerant bacteria play pioneering roles in the process. Specifically, Streptococcus mutans houses major virulence pathways that enable it to thrive in the oral cavity and cause caries. This pathogen adheres to the tooth substrate, forms biofilms, resists external stress, produces acids, kills closely related species, and survives the acid as well as the host clearance mechanisms. For an organism to be able to confer such virulence, it requires a large and complex gene network which synergise to establish disease. In this review, we have charted how these multi-faceted genes control several caries-related functions of Streptococcus mutans. In a futuristic thinking approach, we also briefly discuss the potential roles of omics and machine learning, to ease the study of non-functional genes that may play a major role and enable the integration of experimental data.
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