Investigation of the dual role of acyl phloroglucinols as a new hope for antibacterial and anti-SARS-CoV-2 agents employing integrated in vitro and multi-phase in silico approaches

Abstract

With the rapid spread of multi-drug-resistant bacteria and more infectious or aggressive variants of SARS-CoV-2, it is critical to develop drugs that can quickly adapt to evolving bacterial and viral mutations. In this study, encouraged by nature, we synthesized a series of phloroglucinol (PG) derivatives, acyl phloroglucinols (ACPLs) 2a-4c by mimicking the structure of the natural antifungal 2,4-diacetylphloroglucinol 3a (2,4-DAPG). According to the quantum chemical calculation, these compounds were expected to be exceptionally favourable for intermolecular interaction with protein receptors. Intriguingly, the in vitro study of Staphylococcus aureus (S. aureus) ATCC 25923 and Escherichia coli (E. coli) ATCC 25922, showed that the four ACPLs 3a–4a had good antibacterial activity and selectivity against gram-positive bacteria, S. aureus. These results were then supported by in silico molecular docking and molecular dynamics simulations (MDs) between these potent compounds and the S. aureus FtsA protein (PDB ID: 3WQU). Furthermore, with the aid of the knowledge base Virus-CKB along with the molecular docking study, it was found that the three ACPLs 4a–4c showed potential inhibitors against SARS-CoV-2 PL^pro (PDB ID: 7CMD). Additionally, 100 ns of MDs was carried out in order to assess the stability behaviour of ACPLs at the docked site. Moreover, in silico ADME/T and drug likeness of all studied ACPLs were also predicted. Finally, shape-based screening of FDA-approved drugs was performed using the most prominent synthesized ACPLs as a template, enabling us to include several medications that could be utilized as antibacterial and antiviral drug candidates.

Communicated by Ramaswamy H. Sarma

Keywords:

• 2,4-DAPG
• ACPLs
• FtsA protein
• phloroglucinol
• SARS-CoV-2

Disclosure statement

No potential conflict of interest was reported by the authors.

Author contributions

Each author has made a significant contribution to this research. Conceptualization, material preparation, synthesis, data collection and analysis: Wahyu Eko Prasetyo. Antibacterial assay and formal analysis: Bram Triadmojo and Septin Dwi Anggraini. Project administration, Funding acquisition, and Supervision: Triana Kusumaningsih. Supervision: Soerya Dewi Marliyana, and Mauildan Firdaus. The first draft of the manuscript was written by Wahyu Eko Prasetyo and all the authors commented on the previous version of the manuscript. All authors read and approved the final manuscript.

Additional information

Funding

This work was supported by the Institute of Research and Community of Services Sebelas Maret University under grant number 260/UN27.22/HK.07.00/2021.