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Anti-MRSA activity of chlorophenyl pyrrolo benzodiazepines compound

The Journal of Antibiotics volume 77, pages 589–599 (2024)Cite this article

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Abstract

Antibiotic resistant is the major concern in public health to control the infectious diseases. MRSA (Methicillin-resistant Staphylococcus aureus) is a significant concern in healthcare settings due to its resistance to many antibiotics, including methicillin and other beta-lactams. MRSA infection difficult to treat and increases the risk of complications. Here, we have tested a series of highly condensed heterocyclic derivatives of pyrrolo[1,2-a][1,4]benzodiazepines. Compounds were tested against both, Gram-positive bacteria, Staphylococcus aureus and S. epidermidis, and Gram-negative bacteria, Escherichia coli and Pseudomonas aeruginosa, to assess the antimicrobial efficacy. Compared to Gram-negative bacteria, compounds showed much stronger antibacterial activity against Gram-positive bacteria. SM-5 [Ethyl2-(7-(4-chlorophenyl)-4-methoxy-6,7,8,13-tetrahydro-5H-benzo[e]benzo[5,6][1,4]diazepino[2,1-a]isoindol-15-yl)acetate] derivative was selected as best on the basis of higher therapeutic index among the tested compounds, showed MIC value of 7.81 µg. ml−1 against Staphylococcus strains. Molecular docking analysis between cell wall biosynthesis protein of S. aureus and SM-5 revealed that PBP2a showed the highest binding energy (−8.3 Kcal mol−1), followed by beta-lactam-inducible PBP4 (−7.7 Kcal mol−1), and lipoteichoic acid synthase (−7.5 Kcal mol−1) which is comparably higher than methicillin. Ground state energy calculations by DFT analysis revealed that compound SM-5 and SM-6, almost have equal electronegativity 0.11018 au which also satisfy the quality of the compound reactivity. Analysis of their biofilm inhibition in vitro and in silico toxicity analysis demonstrated their substantial potential to be a kind of future lead antibiotic.

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References

  1. Shigemura K, Osawa K, Mukai A, Yoshida H, Fujisawa M, Arakawa S. Anti-MRSA drug use and antibiotic susceptibilities of MRSA at a university hospital in Japan from 2007 to 2011. J Antibiot. 2013;66:273–6.

    Article  CAS  Google Scholar 

  2. Mandal SM, Ghosh AK, Pati BR. Dissemination of antibiotic resistance in methicillin-resistant Staphylococcus aureus and vancomycin-resistant S. aureus strains isolated from hospital effluents. Am J Infect Control. 2015;43:e87–8.

    Article  CAS  PubMed  Google Scholar 

  3. Kali A. Antibiotics and bioactive natural products in treatment of methicillin resistant Staphylococcus aureus: A brief review. Pharmacogn Rev. 2015;9:29–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Norouzi H, Rabbani Khorasgani M, Danesh A. Anti-MRSA activity of a bioactive compound produced by a marine Streptomyces and its optimization using statistical experimental design. Iran J Basic Med Sci. 2019;22:1073–84.

    PubMed  PubMed Central  Google Scholar 

  5. Iniyan AM, Jabila Mary TR, Sharmila Joseph FR, Kannan RR, Vincent SGP. Cell wall distracting anti-Methicillin-resistant Staphylococcus aureus compound PVI331 from a marine sponge associated Streptomyces. J Appl Biomed. 2016;14:273–83.

    Article  Google Scholar 

  6. Idhayadhulla A, Kumar RS, Nasser AJA. Synthesis, characterization and antimicrobial activity of new pyrrole derivatives. J Mex Chem Soc. 2011;55:218–23.

    CAS  Google Scholar 

  7. Petri GL, Spanò V, Spatola R, Holl R, Raimondi MV, Barraja P, Montalbano A. Bioactive pyrrole-based compounds with target selectivity. Eur J Med Chem. 2020;208:112783.

    Article  Google Scholar 

  8. Rawat P, Singh RN, Ranjan A, Gautam A, Trivedi S, Kumar M. Study of antimicrobial and antioxidant activities of pyrrole-chalcones. J Mol Struct. 2021;1228:129483.

    Article  CAS  Google Scholar 

  9. Duggineni S, Sawant D, Saha B, Kun B. Application of modified Pictet–Spengler reaction for the synthesis of thiazolo- and pyrazolo-quinolines. Tetrahedron, 2006; 62: 3228.

  10. Youn SW. Development of the Pictet−Spengler Reaction Catalyzed by AuCl3/AgOTf. J Org Chem. 2006;71:2521–3.

    Article  CAS  PubMed  Google Scholar 

  11. Katte TA, Reekie TA, Jorgensen WT, Kassiou M. The formation of seven-membered heterocycles under Mild Pictet–Spengler conditions: a route to Pyrazolo[3,4]benzodiazepines. J Org Chem 2016;81:4883.

    Article  CAS  PubMed  Google Scholar 

  12. Giovanna LP, Virginia S, Roberto S, Ralph H, Maria VR, Paola B, lessandra MA. Bioactive pyrrole-based compounds with target selectivity. Eur. J Med Chem. 2020;208:112783.

  13. Ali SA, Mondal SK, Das T, Manna SK, Bera A, Dafadar D, Naskar S, Molla MR, Samanta S. One-pot tandem cyclisation to pyrrolo [1, 2-a][1, 4] benzodiazepines: a modified approach to the Pictet–Spengler reaction. Org Biomol Chem. 2019;17:4652–62.

    Article  CAS  PubMed  Google Scholar 

  14. Mandal SM, Migliolo L, Silva ON, Fensterseifer IC, Faria-Junior C, Dias SC, Basak A, Hazra TK, Franco OL. Controlling resistant bacteria with a novel class of β-lactamase inhibitor peptides: from rational design to in vivo analyses. Sci Rep. 2014;4:6015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Mishra A, Gauri SS, Mukhopadhyay SK, Chatterjee S, Das SS, Mandal SM, Dey S. Identification and structural characterization of a new pro-apoptotic cyclic octapeptide cyclosaplin from somatic seedlings of Santalum album L. Peptides. 2014;54:148–58.

    Article  CAS  PubMed  Google Scholar 

  16. Silva SS, Carvalho JWP, Aires CP, Nitschke M. Disruption of Staphylococcus aureus biofilms using rhamnolipid biosurfactants. J Dairy Sci. 2017;100:7864–73.

    Article  Google Scholar 

  17. Vazquez V, Víctor H, Hernández S, Manuel A, Velázquez S, Ana M, Rosales HM, Leyva R, Marco A, Prado O, María G, Muñoz G, Marco A, Alba HF, Abrego V, Cruz AD, Angeles E. Molecular Modeling and Synthesis of Ethyl Benzyl Carbamates as Possible Ixodicide Activity Computational Chemistry 2018;7:1.

  18. Andreana PR, Liu CC, Schreiber SL. Stereochemical control of the Passerini reaction. Org Lett. 2004;6:4231–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Katte TA, Reekie TA, Jorgensen WT, Kassiou M. The formation of seven-membered heterocycles under Mild Pictet–Spengler conditions: a route to Pyrazolo [3, 4] benzodiazepines. J Org Chem. 2016;81:4883–9.

    Article  CAS  PubMed  Google Scholar 

  20. Gholap SS. Pyrrole: an emerging scaffold for construction of valuable therapeutic agents. Eur J Med Chem. 2016;110:13–31.

    Article  CAS  PubMed  Google Scholar 

  21. Roy A, Mahata D, Paul D, Korpole S, Franco OL, Mandal SM. Purification, biochemical characterization and self-assembled structure of a fengycin-like antifungal peptide from Bacillus thuringiensis strain SM1. Front Microbiol. 2013;4:332.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Archer NK, Mazaitis MJ, Costerton JW, Leid JG, Powers ME, Shirtliff ME. Staphylococcus aureus biofilms: properties, regulation, and roles in human disease. Virulence. 2011;2:445–59.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Mandal S, Roy A, Mahata D. Functional and structural insights on self-assembled nanofiber-based novel antibacterial ointment from antimicrobial peptides, bacitracin and gramicidin S. J Antibiot. 2014;67:771–5.

    Article  CAS  Google Scholar 

  24. Chowdhury T, Dutta J, Roymahapatra G, Mandal SM. In Silico identification of a potent arsenic based lead drug di-phenyl phenoxy roxarsone against SARS-CoV-2. J Indian Chem Soc. 2020;97:1279–85.

    CAS  Google Scholar 

  25. Ghosh A, Roymahapatra G, Paul D, Mandal SM. Theoretical analysis of bacterial efflux pumps inhibitors: Strategies in-search of competent molecules and develop next. Comput Biol Chem. 2020;87:107275.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Bioscience and Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur, 721302, WB, India

    Suresh K. Mondal & Santi M. Mandal

  2. Department of Botany, Netaji Mahavidyalaya, Arambagh, Hooghly, WB, India

    Sk Aftabul Alam

  3. Department of Applied Sciences, Haldia Institute of Technology, Haldia, 721657, India

    Gourisankar Roymahapatra

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  1. Suresh K. Mondal
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  2. Sk Aftabul Alam
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  4. Santi M. Mandal
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Correspondence to Santi M. Mandal.

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Mondal, S.K., Alam, S.A., Roymahapatra, G. et al. Anti-MRSA activity of chlorophenyl pyrrolo benzodiazepines compound. J Antibiot 77, 589–599 (2024). https://doi.org/10.1038/s41429-024-00747-x

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