Teicoplanin is a natural lipoglycopeptide antibiotic with a similar activity spectrum as vancomycin; however, it has with the added benefit to the patient of low cytotoxicity. Both teicoplanin and vancomycin antibiotics are actively used in medical practice in the prophylaxis and treatment of severe life-threatening infections caused by gram-positive bacteria, including methicillin-resistant Staphylococcus aureus, Enterococcus faecium and Clostridium difficile. The expression of vancomycin Z (vanZ), encoded either in the vancomycin A (vanA) glycopeptide antibiotic resistance gene cluster or in the genomes of E. faecium, as well as Streptococcus pneumoniae and C. difficile, was shown to specifically compromise the antibiotic efficiency through the inhibition of teicoplanin binding to the bacterial surface. However, the exact mechanisms of this action and protein structure remain unknown. In this study, the three-dimensional structure of VanZ from E. faecium EnGen0191 was predicted by using the I-TASSER web server. Based on the VanZ structure, a benzimidazole based ligand was predicted to bind to the VanZ by molecular docking. Importantly, this new ligand, named G3K, was further confirmed to specifically inhibit VanZ-mediated resistance to teicoplanin in vivo.

• Klíčová slova
• Enterococcus faecium, MD simulation, Staphylococcus aureus, antibiotic resistance, benzimidazole, docking, ligands, lipoglycopeptide antibiotic, teicoplanin VanZ,
• MeSH
• antibakteriální látky farmakologie   MeSH
• bakteriální léková rezistence účinky léků   MeSH
• bakteriální proteiny metabolismus   MeSH
• grampozitivní bakteriální infekce farmakoterapie   MeSH
• grampozitivní bakterie účinky léků   MeSH
• lidé MeSH
• lipoglykopeptidy farmakologie   MeSH
• mikrobiální testy citlivosti metody   MeSH
• simulace molekulového dockingu metody   MeSH
• teikoplanin farmakologie   MeSH
• vankomycin farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antibakteriální látky MeSH
• bakteriální proteiny MeSH
• lipoglykopeptidy MeSH
• teikoplanin MeSH
• vankomycin MeSH

The SARS-CoV-2 virus is highly contagious to humans and has caused a pandemic of global proportions. Despite worldwide research efforts, efficient targeted therapies against the virus are still lacking. With the ready availability of the macromolecular structures of coronavirus and its known variants, the search for anti-SARS-CoV-2 therapeutics through in silico analysis has become a highly promising field of research. In this study, we investigate the inhibiting potentialities of triazole-based compounds against the SARS-CoV-2 main protease (Mpro). The SARS-CoV-2 main protease (Mpro) is known to play a prominent role in the processing of polyproteins that are translated from the viral RNA. Compounds were pre-screened from 171 candidates (collected from the DrugBank database). The results showed that four candidates (Bemcentinib, Bisoctrizole, PYIITM, and NIPFC) had high binding affinity values and had the potential to interrupt the main protease (Mpro) activities of the SARS-CoV-2 virus. The pharmacokinetic parameters of these candidates were assessed and through molecular dynamic (MD) simulation their stability, interaction, and conformation were analyzed. In summary, this study identified the most suitable compounds for targeting Mpro, and we recommend using these compounds as potential drug molecules against SARS-CoV-2 after follow up studies.

• Klíčová slova
• MD simulation, SARS-CoV-2, docking, drug, main protease, triazole,
• MeSH
• antivirové látky chemie   metabolismus   terapeutické užití   MeSH
• benzocyklohepteny chemie   metabolismus   MeSH
• chemické databáze MeSH
• COVID-19 virologie   MeSH
• farmakoterapie COVID-19 MeSH
• inhibitory proteas chemie   metabolismus   terapeutické užití   MeSH
• koronavirové proteasy 3C antagonisté a inhibitory   metabolismus   MeSH
• kvantitativní vztahy mezi strukturou a aktivitou MeSH
• lidé MeSH
• ligandy MeSH
• poločas MeSH
• SARS-CoV-2 enzymologie   izolace a purifikace   MeSH
• simulace molekulární dynamiky MeSH
• simulace molekulového dockingu MeSH
• triazoly chemie   metabolismus   terapeutické užití   MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 3C-like proteinase, SARS-CoV-2 MeSH Prohlížeč
• antivirové látky MeSH
• bemcentinib MeSH Prohlížeč
• benzocyklohepteny MeSH
• inhibitory proteas MeSH
• koronavirové proteasy 3C MeSH
• ligandy MeSH
• triazoly MeSH

An inexorable switch from antibiotics has become a major desideratum to overcome antibiotic resistance. Bacteriocin from Lactobacillus casei, a cardinal probiotic was used to design novel antibacterial peptides named as Probiotic Bacteriocin Derived and Modified (PBDM) peptides (PBDM1: YKWFAHLIKGLC and PBDM2: YKWFRHLIKKLC). The loop-shaped 3D structure of peptides was characterized in silico via molecular dynamics simulation as well as biophysically via spectroscopic methods. Thereafter, in vitro results against multidrug resistant bacterial strains and hospital samples demonstrated the strong antimicrobial activity of PBDM peptides. Further, in vivo studies with PBDM peptides showed downright recovery of balb/c mice from Vancomycin Resistant Staphylococcus aureus (VRSA) infection to its healthy condition. Thereafter, in vitro study with human epithelial cells showed no significant cytotoxic effects with high biocompatibility and good hemocompatibility. In conclusion, PBDM peptides displayed significant antibacterial activity against certain drug resistant bacteria which cause infections in human beings. Future analysis are required to unveil its mechanism of action in order to execute it as an alternative to antibiotics.

• Klíčová slova
• antibacterial peptides, antibiotics, bacteria, infections, multidrug resistance,
• Publikační typ
• časopisecké články MeSH