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Flavonoids as Potential anti-MRSA Agents through Modulation of PBP2a: A Computational and Experimental Study.

ABSTRACT: Recently, the interest in plant-derived antimicrobial agents has increased. However, there are no sufficient studies dealing with their modes of action. Herein, we investigate an in-house library of common plant-based phenolic compounds for their potential antibacterial effects against the methicillin-resistant Staphylococcus aureus (MRSA), a widespread life-threatening superbug. Flavonoids, which are considered major constituents in the plant kingdom, were found to be a promising class of compounds against MRSA, particularly the non-glycosylated ones. On the other hand, the glycosylated derivatives, along with the flavonolignan silibinin A, were able to restore the inhibitory activity of ampicillin against MRSA. To explore the mode of action of this class, they were subjected to an extensive inverse virtual screening (IVS), which suggested penicillin-binding protein 2a (PBP2a) as a possible target that mediates both the antibacterial and the antibiotic-synergistic effects of this class of compounds. Further molecular docking and molecular dynamic simulation experiments were conducted to support the primary IVS and the in vitro results and to study their binding modes with PBP2a. Our findings shed a light on plant-derived natural products, notably flavonoids, as a promising and readily available source for future adjuvant antimicrobial therapy against resistant strains.

SUBMITTER: Alhadrami HA

PROVIDER: S-EPMC7559925 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Flavonoids as Potential anti-MRSA Agents through Modulation of PBP2a: A Computational and Experimental Study.

Alhadrami Hani A HA Hamed Ahmed A AA Hassan Hossam M HM Belbahri Lassaad L Rateb Mostafa E ME Sayed Ahmed M AM

Antibiotics (Basel, Switzerland) 20200831 9

Recently, the interest in plant-derived antimicrobial agents has increased. However, there are no sufficient studies dealing with their modes of action. Herein, we investigate an in-house library of common plant-based phenolic compounds for their potential antibacterial effects against the methicillin-resistant <i>Staphylococcus aureus</i> (MRSA), a widespread life-threatening superbug. Flavonoids, which are considered major constituents in the plant kingdom, were found to be a promising class o ...[more]

PMID: 32878266

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Project description:Methicillin-resistant Staphylococcus aureus (MRSA) is one of the leading causes of bacterial infections in both healthcare and community settings. MRSA can acquire resistance to any current antibiotic, which has major implications for its current and future treatment options. As such, it is globally a major focus for infection control efforts. The mechanical rigidity provided by peptidoglycans in the bacteria cell walls makes it a promising target for broad-spectrum antibacterial drug discovery. The development of drugs that can target different stages of the synthesis of peptidoglycan in MRSA may compromise the integrity of its cell wall and consequently result in the rapid decline of diseases associated with this drug-resistant bacteria. The present study is aimed at screening natural products with known in vitro activities against MRSA to identify their potential to inhibit the proteins involved in the biosynthesis of the peptidoglycan cell wall. A total of 262 compounds were obtained when a literature survey was conducted on anti-MRSA natural products (AMNPs). Virtual screening of the AMNPs was performed against various proteins (targets) that are involved in the biosynthesis of the peptidoglycan (PPC) cell wall using Schrödinger software (release 2020-3) to determine their binding affinities. Nine AMNPs were identified as potential multitarget inhibitors against peptidoglycan biosynthesis proteins. Among these compounds, DB211 showed the strongest binding affinity and interactions with six protein targets, representing three stages of peptidoglycan biosynthesis, and thus was selected as the most promising compound. The MD simulation results for DB211 and its proteins indicated that the protein-ligand complexes were relatively stable over the simulation period of 100 ns. In conclusion, DB211 showed the potential to inhibit six proteins involved in the biosynthesis of the peptidoglycan cell wall in MRSA, thus reducing the chance of MRSA developing resistance to this compound. Therefore, DB211 provided a starting point for the design of new compounds that can inhibit multiple targets in the biosynthesis of the peptidoglycan layer in MRSA.

Dataset Information

Flavonoids as Potential anti-MRSA Agents through Modulation of PBP2a: A Computational and Experimental Study.

Publications

Flavonoids as Potential anti-MRSA Agents through Modulation of PBP2a: A Computational and Experimental Study.

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