Skip to main content

Advertisement

SpringerLink
Log in

Reduction of Bacterial Folic Acid Production and Cell Membrane Disruption of Klebsiella pneumoniae by Two Amino Substituted Pyridyl Compounds: An Experimental and In Silico Approach

  • Short Communication
  • Published:
Chemistry Africa Aims and scope Submit manuscript

Abstract

As bacterial resistance increases, more effective antibiotics are needed, necessitating drug discovery research. Therefore, in this paper we discuss the potential modes of action of two organic compounds, 4-(pyridin-4-ylmethoxy)aniline (L2) and pyridin-4-ylmethyl 4-aminobenzoate (L1) as antibacterial agents against Klebsiella pneumoniae, which were both studied in vitro. The folic acid production assay showed that the compound L1 was more effective than L2 and silver sulfadiazine AgSD (control) at inhibiting folic acid production. The compounds had better binding scores than the DHPS binding substrate para-amino benzoic acid (PABA), according to the molecular docking studies, and L1 was able to bind to the PABA binding pocket, demonstrating competitive antagonism. Moreover, the molecular docking data for AgSD and L1 were found to be in good agreement with the corresponding experimental results. On the other hand, AgSD was better in affecting the integrity of the bacterial membrane as this is its primary mode of action. L2 and L1 showed a significant amount of AKP release than the vehicle control, suggesting that this may also be a potential mode of action of compounds with their pharmacophores. The binding energies of these compounds corroborated with the AKP release data, these were − 5.70, − 5.52 and − 5.27 kcal/mol for AgSD, L1 and L2 respectively, showing that AgSD was the best followed by L1 and L2.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Scheme 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Data availability

The corresponding author will provide the datasets used and analyzed during the present work upon reasonable request.

References

  1. Martin RM, Bachman MA (2018) Colonization, infection, and the accessory genome of Klebsiella pneumoniae. Front Cell Infect Microbiol 8:1–15

    Article  Google Scholar 

  2. Hassan Y, Aminu M, Aminu I, Sharif A (2022) Klebsiella pneumoniae: a case report of pneumonia and cephalosporins resistant clinical isolate. BJMLS 7:128–137

    Google Scholar 

  3. Moo CL, Yang SK, Yusoff K, Ajat M, Thomas W, Abushelaibi A, Lim S-H-E, Lai K-S (2020) Mechanisms of antimicrobial resistance (AMR) and alternative approaches to overcome AMR. Curr Drug Discov Technol 17:430–447

    Article  CAS  PubMed  Google Scholar 

  4. Takenaka T (2001) Classical vs reverse pharmacology in drug discovery. BJU Int 88:7–10

    Article  CAS  PubMed  Google Scholar 

  5. Merz KM Jr, Ringe D, Reynolds CH (2010) Drug design: structure-and ligand-based approaches. Cambridge University Press, Cambridge

    Book  Google Scholar 

  6. Matshwele JTP, Odisitse S, Mazimba O, Nareetsile F, Julius LG, Keitumetse D (2022) Crystal structure of pyridin-4-ylmethyl 4-nitrobenzoate. X-Ray Struct Anal Online 38:7–8

    Article  CAS  Google Scholar 

  7. Matshwele JTP, Jongman M, Koobotse MO, Mazimba O, Mapolelo D, Nkwe DO, Nareetsile F, Odisitse S (2022) Synthesis, characterization of nitro or amino substituted pyridyl ligands bridged by an ester or ether bond, and their antibacterial assessment against drug resistant bacteria. Results Chem 4:100401

    Article  CAS  Google Scholar 

  8. Bermingham A, Derrick JP (2002) The folic acid biosynthesis pathway in bacteria: evaluation of potential for antibacterial drug discovery. BioEssays 24:637–648

    Article  CAS  PubMed  Google Scholar 

  9. Férriz JM, Vinšová J (2010) Prodrug design of phenolic drugs. Curr Pharm Des 16:2033–2052

    Article  PubMed  Google Scholar 

  10. Beaumont K, Webster R, Gardner I, Dack K (2003) Design of Ester prodrugs to enhance oral absorption of poorly permeable compounds: challenges to the discovery scientist. Curr Drug Metab 4:461–485

    Article  CAS  PubMed  Google Scholar 

  11. Ling Y, Hao Z-Y, Liang D, Zhang C-L, Liu Y-F, Wang Y (2021) The expanding role of pyridine and dihydropyridine scaffolds in drug design. Drug Des Devel Ther 15:4289–4338

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Horchani M, Hajlaoui A, Harrath AH, Mansour L, Ben Jannet H, Romdhane A (2020) New pyrazolo-triazolo-pyrimidine derivatives as antibacterial agents: Design and synthesis, molecular docking and DFT studies. J Mol Struct 1199:127007

    Article  CAS  Google Scholar 

  13. Horchani M, Edziri H, Harrath AH, Ben Jannet H, Romdhane A (2022) Access to new Schiff bases tethered with pyrazolopyrimidinone as antibacterial agents: Design and synthesis, molecular docking and DFT analysis. J Mol Struct 1248:131523

    Article  CAS  Google Scholar 

  14. Taylor TJ, Seitz EP, Fox P, Fischler GE, Fuls JL, Weidner PL (2004) Physicochemical factors affecting the rapid bactericidal efficacy of the phenolic antibacterial triclosan. Int J Cosmet Sci 26:111–116

    Article  CAS  PubMed  Google Scholar 

  15. Matshwele JTP, Odisitse S, Mazimba O, Julius LG, Mogatwe T, Nareetsile F (2022) Synthesis and crystal structure of pyridin-4-ylmethyl 4-aminobenzoate, C13H12N2O2. Crystallogr Rep 67:1203–1206

    Article  CAS  Google Scholar 

  16. Pompei A, Cordisco L, Amaretti A, Zanoni S, Matteuzzi D, Rossi M (2007) Folate production by bifidobacteria as a potential probiotic property. Appl Environ Microbiol 73:179–185

    Article  CAS  PubMed  Google Scholar 

  17. Xiao X-N, Wang F, Yuan Y-T, Liu J, Liu Y-Z, Yi X (2019) Antibacterial activity and mode of action of dihydromyricetin from ampelopsis grossedentata leaves against food-borne bacteria. Molecules 24:2831

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Stephens PJ, Devlin FJ, Chabalowski CF, Frisch MJ (1994) Ab initio calculation of vibrational absorption and circular dichroism spectra using density functional force fields. J Phys Chem 98:11623–11627

    Article  CAS  Google Scholar 

  19. Lee C, Yang W, Parr RG (1988) Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density. Phys Rev B 37:785–789

    Article  CAS  Google Scholar 

  20. Becke AD (1992) Density-functional thermochemistry. I. The effect of the exchange-only gradient correction. J Chem Phys 96:2155–2160

    Article  CAS  Google Scholar 

  21. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Montgomery JA Jr., Vreven T, Kudin KN, Burant JC, Millam JM, Lyengar SS, Tomasi J, Barone V, Mennucci B, Cossi M, Scalmani G, Rega N, Petersson GA, Nakatsuji H, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Klene M, Li X, Knox JE, Hratchian HP, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Ayala PY, Morokuma K, Voth GA, Salvador P, Dannenberg JJ, Zakrzewski VG, Dapprich S, Daniels AD, Strain MC, Farkas O, Malick DK, Rabuck AD, Raghavachari K, Foresman JB, Ortiz JV, Cui Q, Baboul AG, Clifford S, Cioslowski J, Stefanov BB, Liu G, Liashenko A, Piskorz P, Komaromi I, Martin RL, Fox DJ, Keith T, Al-Laham MA, Peng CY, Nanayakkara A, Challacombe M, Gill PMW, Johnson B, Chen W, Wong MW, Gonzalez C, Pople JA (2016) Gaussian 16 Revision C. 01. 2016. Gaussian Inc. Wallingford, p 421.

  22. Allouche A-R (2011) Gabedit-A graphical user interface for computational chemistry softwares. J Comput Chem 32:174–182

    Article  CAS  PubMed  Google Scholar 

  23. Sanner MF (1999) Python: a programming language for software integration and development. J Mol Graph Model 17:57–61

    CAS  PubMed  Google Scholar 

  24. Systèmes D (2020) BIOVIA, discovery studio visualizer, release 2019. San Diego: Dassault Systèmes.

  25. Kikuchi T, Gontani S, Miyanaga K, Kurata T, Akatani Y, Matsumoto S (2019) Crystal structure of benzyl 2-naphthyl ether, a sensitiser for thermal paper. Acta Crystallogr E Crystallogr Commun 75:242–245

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. DrugBank Online Silver sulfadiazine. https://go.drugbank.com/drugs/DB05245. Accessed 17 Dec 2022

  27. Azzam RA, Elsayed RE, Elgemeie GH (2020) Design, synthesis, and antimicrobial evaluation of a new series of N-sulfonamide 2-pyridones as dual inhibitors of DHPS and DHFR enzymes. ACS Omega 5:10401–10414

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Fernández-Villa D, Aguilar MR, Rojo L (2019) Folic acid antagonists: antimicrobial and immunomodulating mechanisms and applications. Int J Mol Sci 20:4996

    Article  PubMed  PubMed Central  Google Scholar 

  29. Brown GM The biosynthesis of folic acid. 2. Inhibition by sulfonamides. Journal of Biological Chemistry 237:536–540.

  30. March C, Moranta D, Regueiro V, Llobet E, Tomás A, Garmendia J, Bengoechea JA (2011) Klebsiella pneumoniae outer membrane protein A is required to prevent the activation of airway epithelial cells. J Biol Chem 286:9956–9967

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Galbadage T, Liu D, Alemany LB, Pal R, Tour JM, Gunasekera RS, Cirillo JD (2019) Molecular nanomachines disrupt bacterial cell wall, increasing sensitivity of extensively drug-resistant Klebsiella pneumoniae to meropenem. ACS Nano 13:14377–14387

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. O’Driscoll NH, Cushnie TT, Matthews KH, Lamb AJ (2018) Colistin causes profound morphological alteration but minimal cytoplasmic membrane perforation in populations of Escherichia coli and Pseudomonas aeruginosa. Arch Microbiol 200:793–802

    Article  PubMed  PubMed Central  Google Scholar 

  33. Tang H, Chen W, Dou Z-M, Chen R, Hu Y, Chen W, Chen H (2017) Antimicrobial effect of black pepper petroleum ether extract for the morphology of Listeria monocytogenes and Salmonella typhimurium. J Food Sci Technol 54:2067–2076

    Article  PubMed  PubMed Central  Google Scholar 

  34. Guo L, Zhang F, Wang X, Chen H, Wang Q, Guo J, Cao X, Wang L (2019) Antibacterial activity and action mechanism of questin from marine Aspergillus flavipes HN4–13 against aquatic pathogen Vibrio harveyi. 3 Biotech 9:14

    Article  PubMed  PubMed Central  Google Scholar 

  35. Drews J (2000) Drug discovery: a historical perspective. Science (1979) 287:1960–1964

    CAS  Google Scholar 

  36. Kuntz ID (1992) Structure-based strategies for drug design and discovery. Science (1979) 257:1078–1082

    CAS  Google Scholar 

  37. May KL, Grabowicz M (2018) The bacterial outer membrane is an evolving antibiotic barrier. Proc Natl Acad Sci 115:8852–8854

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Doménech-Sánchez A, Hernández-Allés S, Martínez-Martínez L, Benedí VJ, Albertí S (1999) Identification and characterization of a new porin gene of Klebsiella pneumoniae : its role in β-lactam antibiotic resistance. J Bacteriol 181:2726–2732

    Article  PubMed  PubMed Central  Google Scholar 

  39. Wong JLC, Romano M, Kerry LE, Kwong H-S, Low W-W, Brett SJ, Clements A, Beis K, Frankel G (2019) OmpK36-mediated Carbapenem resistance attenuates ST258 Klebsiella pneumoniae in vivo. Nat Commun 10:3957

    Article  PubMed  PubMed Central  Google Scholar 

  40. Vinnicombe HG, Derrick JP (1999) Dihydropteroate synthase from. Streptococcus pneumoniae: characterization of substrate binding order and sulfonamide inhibition. Biochem Biophys Res Commun 258:752–757

    Article  CAS  PubMed  Google Scholar 

  41. Roland S, Ferone R, Harvey RJ, Styles VL, Morrison RW (1979) The characteristics and significance of sulfonamides as substrates for Escherichia coli dihydropteroate synthase. J Biol Chem 254:10337–10345

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to express their appreciation to the BIUST Office of Research, Development, and Innovation for the research Grant S00326 and the University of Botswana Office of Research and Development research Grant R1220.

Author information

Authors and Affiliations

  1. Faculty of Science, Botswana International University of Science and Technology, Private Bag 16, Palapye, Botswana

    James T. P. Matshwele, Ofentse Mazimba, David O. Nkwe & Sebusi Odisitse

  2. Faculty of Science, University of Botswana, Private Bag 0704, Gaborone, Botswana

    Mosimanegape Jongman, Taye B. Demissie, Daphne Mapolelo, Lebogang G. Julius & Florence Nareetsile

  3. Faculty of Health Sciences, University of Botswana, Private Bag, 00712, Gaborone, UB, Botswana

    Moses O. Koobotse & Keagile Bati

  4. Faculty of Engineering and Technology, Botho University, Gaborone, Botswana, PO Box 501564, Gaborone, Botswana

    James T. P. Matshwele

Authors
  1. James T. P. Matshwele
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mosimanegape Jongman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Taye B. Demissie
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Moses O. Koobotse
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ofentse Mazimba
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Daphne Mapolelo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Keagile Bati
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Lebogang G. Julius
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. David O. Nkwe
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Florence Nareetsile
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Sebusi Odisitse
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to James T. P. Matshwele or Sebusi Odisitse.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 1297 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Matshwele, J.T.P., Jongman, M., Demissie, T.B. et al. Reduction of Bacterial Folic Acid Production and Cell Membrane Disruption of Klebsiella pneumoniae by Two Amino Substituted Pyridyl Compounds: An Experimental and In Silico Approach. Chemistry Africa 6, 2725–2735 (2023). https://doi.org/10.1007/s42250-023-00662-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s42250-023-00662-y

Keywords

Search

Navigation