RESUMO
Histone deacetylase 3 (HDAC3), a Zn2+-dependent class I HDACs, contributes to numerous disorders such as neurodegenerative disorders, diabetes, cardiovascular disease, kidney disease and several types of cancers. Therefore, the development of novel and selective HDAC3 inhibitors might be promising to combat such diseases. Here, different classification-based molecular modelling studies such as Bayesian classification, recursive partitioning (RP), SARpy and linear discriminant analysis (LDA) were conducted on a set of HDAC3 inhibitors to pinpoint essential structural requirements contributing to HDAC3 inhibition followed by molecular docking study and molecular dynamics (MD) simulation analyses. The current study revealed the importance of hydroxamate function for Zn2+ chelation as well as hydrogen bonding interaction with Tyr298 residue. The importance of hydroxamate function for higher HDAC3 inhibition was noticed in the case of Bayesian classification, recursive partitioning and SARpy models. Also, the importance of substituted thiazole ring was revealed, whereas the presence of linear alkyl groups with carboxylic acid function, any type of ester function, benzodiazepine moiety and methoxy group in the molecular structure can be detrimental to HDAC3 inhibition. Therefore, this study can aid in the design and discovery of effective novel HDAC3 inhibitors in the future.
Assuntos
Teorema de Bayes , Inibidores de Histona Desacetilases , Histona Desacetilases , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Relação Quantitativa Estrutura-Atividade , Histona Desacetilases/química , Histona Desacetilases/metabolismo , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Análise Discriminante , Estrutura MolecularRESUMO
Bacteria commonly adhere to surfaces and produce polymeric material to encase the attached cells to form communities called biofilms. Within these biofilms, bacteria can appear to be many times more resistant to antibiotics or disinfectants. This systematic review explores the prevalence and microbial profile associated with biofilm production of bacteria isolated from endotracheal tubes and its associations with antimicrobial resistance. A comprehensive search was performed on databases PubMed, Embase, and Google Scholar for relevant articles published between 1st January 2000 and 31st December 2022. The relevant articles were exported to Mendeley Desktop 1.19.8 and screened by title and abstract, followed by full text screening based on the eligibility criteria of the study. Quality assessment of the studies was performed using the Newcastle-Ottawa Scale (NOS) customized for cross-sectional studies. Furthermore, the prevalence of antimicrobial resistance in biofilm-producers isolated from endotracheal tube specimens was investigated. Twenty studies encompassing 981 endotracheal tubes met the eligibility criteria. Pseudomonas spp. and Acinetobacter spp. were predominant isolates among the biofilm producers. These biofilms provided strong resistance against commonly used antibiotics. The highest resistance rate observed in Pseudomonas spp. was against fluoroquinolones whereas the least resistance was seen against piperacillin-tazobactam. A similar trend of susceptibility was observed in Acinetobacter spp. with a very high resistance rate against fluoroquinolones, third-generation cephalosporins and carbapenems. In conclusion, endotracheal tubes were associated with colonization by biofilm forming bacteria with varying levels of antimicrobial resistance. Biofilms may promote the occurrence of recalcitrant infections in endotracheal tubes which need to be managed with appropriate protocols and antimicrobial stewardship. Research focus should shift towards meticulous exploration of biofilm-associated infections to improve detection and management.