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Updated: May 10, 2025
A Platform of Anti-biofilm Assays Suited to the Exploration of Natural Compound Libraries
Published on: December 27, 2016
Discovery of Novel Antimicrobial-Active Compounds and Their Analogues by In Silico Small Chemical Screening Targeting
Saya Okubo1, Shoki Hirose1, Shunsuke Aoki1
1Department of Bioscience and Bioinformatics, Graduate School of Computer Science and Systems Engineering, Kyushu Institute of Technology, Iizuka 820-8502, Japan.
Abstract:
Methicillin-resistant Staphylococcus aureus is a serious problem in healthcare due to its lethal severe infections and resistance to most antimicrobial agents. The number of new approved antimicrobial agents is declining, and combined with the spread of drug-resistant bacteria, it is predicted that effective antimicrobial agents against multidrug-resistant bacteria will be exhausted. We conducted in silico and in vitro discovery of novel antimicrobial small molecules targeting the SaMurB enzyme involved in cell wall synthesis in Staphylococcus aureus (S. aureus). We performed hierarchical structure-based drug screenings to identify compounds and their analogues using a library of approximately 1.3 million compound structures. In vitro experiments with Staphylococcus epidermidis (S. epidermidis) identified three compounds (SH5, SHa6, and SHa13) that exhibit antibacterial activity. These three compounds do not have toxicity against human-derived cells. SHa13 exhibited remarkable activity (IC50 value =1.64 ± 0.01 µM). The active compound was predicted to bind to the active site of SaMurB by forming a hydrogen bond with Arg188 in both R and S bodies. These data provide a starting point for the development of novel cell wall synthesis inhibitors as antimicrobial agents targeting SaMurB.
Insights
Researchers discovered novel small molecules targeting the SaMurB enzyme to combat drug-resistant Staphylococcus aureus infections. Three compounds, including SHa13, showed antibacterial activity without human cell toxicity, offering a new avenue for antimicrobial drug development.
Area of Science:
- Microbiology
- Drug Discovery
- Biochemistry
Background:
- Methicillin-resistant Staphylococcus aureus (MRSA) poses a significant healthcare threat due to severe infections and antimicrobial resistance.
- Declining antimicrobial agent approvals and rising drug resistance predict a future shortage of effective treatments for multidrug-resistant bacteria.
Purpose of the Study:
- To discover novel antimicrobial small molecules targeting the SaMurB enzyme, crucial for Staphylococcus aureus cell wall synthesis.
- To identify potential drug candidates to address the growing threat of multidrug-resistant bacteria.
Main Methods:
- In silico hierarchical structure-based drug screening of approximately 1.3 million compound structures.
- In vitro antibacterial activity and toxicity assays using Staphylococcus epidermidis and human-derived cells.
Main Results:
- Three compounds (SH5, SHa6, SHa13) demonstrated antibacterial activity against Staphylococcus epidermidis.
- The identified compounds exhibited no toxicity against human-derived cells.
- SHa13 showed potent activity (IC50 = 1.64 ± 0.01 µM) and was predicted to bind to the SaMurB active site via hydrogen bonding with Arg188.
Conclusions:
- The identified compounds, particularly SHa13, represent promising starting points for developing novel SaMurB inhibitors.
- This research offers a potential strategy for creating new antimicrobial agents to combat resistant bacterial infections.
- Targeting bacterial cell wall synthesis through SaMurB inhibition is a viable approach for novel antibiotic development.
