J Chem Inf Model - Identification of novel potential antibiotics against Staphylococcus using structure-based drug screening targeting dihydrofolate reductase.

Tópicos

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Resumo

The emergence of multidrug-resistant Staphylococcus aureus (S. aureus) makes the treatment of infectious diseases in hospitals more difficult and increases the mortality of the patients. In this study, we attempted to identify novel potent antibiotic candidate compounds against S. aureus dihydrofolate reductase (saDHFR). We performed three-step in silico structure-based drug screening (SBDS) based on the crystal structure of saDHFR using a 154,118 chemical compound library. We subsequently evaluated whether candidate chemical compounds exhibited inhibitory effects on the growth of the model bacterium: Staphylococcus epidermidis (S. epidermidis). The compound KB1 showed a strong inhibitory effect on the growth of S. epidermidis. Moreover, we rescreened chemical structures similar to KB1 from a 461,397 chemical compound library. Three of the four KB1 analogs (KBS1, KBS3, and KBS4) showed inhibitory effects on the growth of S. epidermidis and enzyme inhibitory effects on saDHFR. We performed structure-activity relationship (SAR) analysis of active chemical compounds and observed a correlative relationship among the IC50 values, interaction residues, and structure scaffolds. In addition, the active chemical compounds (KB1, KBS3, and KBS4) had no inhibitory effects on the growth of model enterobacteria (E. coli BL21 and JM109 strains) and no toxic effects on cultured mammalian cells (MDCK cells). Results obtained from Protein Ligand Interaction Fingerprint (PLIF) and Ligand Interaction (LI) analyses suggested that all of the active compounds exhibited potential inhibitory effects on mutated saDHFR of the drug-resistant strains. The structural and experimental information concerning these novel chemical compounds will likely contribute to the development of new antibiotics for both wild-type and drug-resistant S. aureus.

Resumo Limpo

emerg multidrugresist staphylococcus aureus s aureus make treatment infecti diseas hospit difficult increas mortal patient studi attempt identifi novel potent antibiot candid compound s aureus dihydrofol reductas sadhfr perform threestep silico structurebas drug screen sbds base crystal structur sadhfr use chemic compound librari subsequ evalu whether candid chemic compound exhibit inhibitori effect growth model bacterium staphylococcus epidermidi s epidermidi compound kb show strong inhibitori effect growth s epidermidi moreov rescreen chemic structur similar kb chemic compound librari three four kb analog kbs kbs kbs show inhibitori effect growth s epidermidi enzym inhibitori effect sadhfr perform structureact relationship sar analysi activ chemic compound observ correl relationship among ic valu interact residu structur scaffold addit activ chemic compound kb kbs kbs inhibitori effect growth model enterobacteria e coli bl jm strain toxic effect cultur mammalian cell mdck cell result obtain protein ligand interact fingerprint plif ligand interact li analys suggest activ compound exhibit potenti inhibitori effect mutat sadhfr drugresist strain structur experiment inform concern novel chemic compound will like contribut develop new antibiot wildtyp drugresist s aureus

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