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Updated: Aug 5, 2026
Biosensor for Detection of Antibiotic Resistant Staphylococcus Bacteria
Published on: May 8, 2013
Drug Repurposing against the PurS Subunit of Phosphoribosylformylglycinamidine Synthase in Methicillin- and
Faryal Ashraf1, M Iqbal Choudhary1,2,3,4, Muhammad Yousuf1
1Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan.
Introduction:
Staphylococcus aureus is the causative agent of mild to severe human infections. The exponential increase in resistance to available antibiotics has created the need to identify new drug targets and develop new drug candidates to combat bacterial infections. The PurS subunit of phosphoribosylformylglycinamidine synthase (synonym FGAM synthase) catalyzes the 4th step of the de novo purine biosynthesis in bacteria, including S. aureus. Purine nucleotides are essential in the bacterial life cycle and are required for growth and survival. Inhibition or disruption of FGAM synthase adversely affects the bacterial life cycle.
Methods:
This study reports cloning, expression, and purification (yield 16.08 mg/mL) of the PurS subunit of FGAM synthase from methicillin- and oxacillin-resistant Staphylococcus aureus, followed by interaction analysis of the PurS subunit with 50 US-FDAapproved drugs, using Saturation Transfer Difference (STD) NMR spectroscopy.
Results:
Among these drugs, tramadol HCl (1), nicotinamide (2), amoxicillin trihydrate (3), hydroxychloroquine sulphate (4), and phenylephrine HCl (5) showed interactions with the PurS subunit of FGAM synthase, using STD-NMR spectroscopy. All 50 drugs were also studied for their effects on thermal destabilization of the PurS subunit using differential scanning fluorimetry; among them, only nicotinamide (2) and drotaverine HCl (6) destabilized the PurS subunit of FGAM synthase. However, drug 6 interacted with the PurS subunit either irreversibly or with strong binding affinity, as no interactions in STD-NMR were observed. Therefore, drugs 1‒5, which showed interactions in STD-NMR, were further computationally studied, revealing comparable docking scores (-2.4 to 0.21) for complexes 1‒5 (PurS subunit, and drugs 1‒5), with substantial binding energies, supporting the experimental findings.
Discussion:
The current study focuses on FGAM synthase, a potential drug target in S. aureus. This is the first report on the identification of drugs that bind the PurS subunit of FGAM synthase using STD-NMR, DSF, and molecular docking. Drugs 1‒6 can be considered potential hits for further studies for drug discovery against infections caused by methicillin- and oxacillin-resistant S. aureus.
Conclusion:
These five hits merit further biochemical and mechanistic studies to validate their therapeutic potential against methicillin- and oxacillin-resistant S. aureus infections.
Insights
This study identified five FDA-approved drugs that interact with the PurS subunit of FGAM synthase, a potential target for combating antibiotic-resistant Staphylococcus aureus infections. These findings offer new avenues for developing novel antibacterial therapies.
Area of Science:
- Microbiology
- Drug Discovery
- Biochemistry
Background:
- Staphylococcus aureus is a major cause of human infections.
- Increasing antibiotic resistance necessitates new drug targets and candidates.
- The PurS subunit of FGAM synthase is crucial for bacterial purine biosynthesis and survival.
Purpose of the Study:
- To identify potential drug candidates targeting the PurS subunit of FGAM synthase in S. aureus.
- To investigate interactions between FDA-approved drugs and the PurS subunit.
- To evaluate the therapeutic potential of identified drug candidates.
Main Methods:
- Cloning, expression, and purification of the S. aureus PurS subunit.
- Saturation Transfer Difference (STD) NMR spectroscopy to analyze drug-PurS interactions.
- Differential Scanning Fluorimetry (DSF) to assess thermal destabilization.
- Computational molecular docking studies.
Main Results:
- Five FDA-approved drugs (tramadol HCl, nicotinamide, amoxicillin trihydrate, hydroxychloroquine sulphate, phenylephrine HCl) showed interactions with the PurS subunit via STD-NMR.
- Nicotinamide and drotaverine HCl destabilized the PurS subunit.
- Computational docking supported experimental findings with comparable scores and binding energies for the five identified drugs.
Conclusions:
- This study is the first to identify drugs binding to the PurS subunit of FGAM synthase using STD-NMR, DSF, and molecular docking.
- The identified drugs (1-5) are potential hits for further drug discovery against S. aureus.
- Further biochemical and mechanistic studies are warranted to validate the therapeutic potential of these hits against resistant S. aureus infections.
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