Molecular Docking and Screening Studies of New Natural Sortase A Inhibitors

To date, multi-drug resistant bacteria represent an increasing health threat, with a high impact on mortality, morbidity, and health costs on a global scale. The ability of bacteria to rapidly and permanently acquire new virulence factors and drug-resistance elements requires the development of new...

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Bibliographic Details
Published in:International journal of molecular sciences 2017-10, Vol.18 (10), p.2217
Main Authors: Nitulescu, Georgiana, Nicorescu, Isabela Madalina, Olaru, Octavian Tudorel, Ungurianu, Anca, Mihai, Dragos Paul, Zanfirescu, Anca, Nitulescu, George Mihai, Margina, Denisa
Format: Article
Language:English
Subjects:
anti-infective
Antiinfectives and antibacterials
Antimicrobial activity
Antimicrobial agents
Bacteria
Daphnia magna
Drug resistance
Energy consumption
Fluorescence
Fluorescence resonance energy transfer
Gram-positive bacteria
Inhibitors
MDR-bacteria
Minimum inhibitory concentration
Molecular docking
Molecular structure
Morbidity
Multidrug resistance
Pathogens
Resistance factors
Sortase
sortase A
Staphylococcus aureus
Toxicity
Virulence
Virulence factors
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Summary:To date, multi-drug resistant bacteria represent an increasing health threat, with a high impact on mortality, morbidity, and health costs on a global scale. The ability of bacteria to rapidly and permanently acquire new virulence factors and drug-resistance elements requires the development of new antimicrobial agents and selection of new proper targets, such as sortase A. This specific bacterial target plays an important role in the virulence of many Gram-positive pathogens, and its inhibition should produce a mild evolutionary pressure which will not favor the development of resistance. A primary screening using a fluorescence resonance energy transfer assay was used to experimentally evaluate the inhibitory activity of several compounds on sortase A. Using molecular docking and structure-activity relationship analyses, several lead inhibitors were identified, which were further tested for antimicrobial activity using the well diffusion test and minimum inhibitory concentration. The toxicity was assessed using the test and used as a future screening filter. Three natural compounds were identified in this study as promising candidates for further development into therapeutically useful anti-infective agents that could be used to treat infections caused by multi-drug resistant bacterial pathogens which include sortase A in their enzymatic set.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms18102217