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The Therapeutic Potential of 4-Methoxy-1-methyl-2-oxopyridine-3-carbamide (MMOXC) Derived from Ricinine on Macrophage Cell Lines Infected with Methicillin-Resistant Strains of Staphylococcus aureus

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Abstract

The incidences of methicillin-resistant strains of Staphylococcus aureus (MRSA) and their survival inside the macrophages are the major attributes of the relapsed infections after antimicrobial therapy, and it is a global problem. In this context, we have previously demonstrated 4-methoxy-1-methyl-2-oxopyridine-3-carbamide (MMOXC), a Ricinine derivative exhibiting anti-S. aureus and anti-biofilm characteristics by competitively inhibiting uridine monophosphate kinase (UMPK), UDP-N-acetyl muramyl pentapeptide ligase (Mur-F), and peptidyl deformylase, (PDF). In the present study, the stability of this competitive inhibitor MMOXC was evaluated by showing its ability to remain bound to the active sites of UMPK, Mur-F, and PDF even after increasing the incubation time, temperature, pH, and substrate concentration. On growing MRSA in fewer concentrations of MMOXC, these strains could not attain resistance to MMOXC and at the same time distinct reductions in the expression of UMPK, Mur-F, and PDF genes were noted. In vitro, infective models were generated by infecting MRSA to RAW 264.7 and human monocyte-derived macrophage (hMDM) cell lines. In these infected cell lines, in spite of increased nitric oxide synthase (NOS), NADPH–P450 reductase, superoxide dismutase, catalase, and peroxidase activities, the MRSA survived. At 640 µM/ml, the concentration of MMOXC penetrated into these infected cells and obliterated MRSA. While treating uninfected macrophage cell lines with MMOXC, no appreciable effect was observed indicating that MMOXC is the most suitable drug for the treatment of infections caused by MRSA.

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Data Availability

The data presented in the manuscript are available from the corresponding author who can be contacted at a reasonable time. Some of the data which are cloning of UMPK, Mur-f, and PDF are available at GenBank (accession no: FJ415072, JX841309, and JX311310).

Abbreviations

ANAE :

Alpha-naphthyl acetate esterase

ATCC :

American Type Culture Collection

BHI :

Brain Heart Infusion

BP medium :

Baird Parker Medium

CA-MRSA :

Community-associated methicillin-resistant S. aureus

CAT :

Catalase

CFU :

Colony-forming unit

d -ala- d -ala :

D-alanine-d-alanine

DMEM :

Dulbecco’s modified Eagle medium

IPTG :

Isopropyl-β-d-thiogalactopyranoside

hMDMs :

Human monocyte-derived macrophages

I :

Inhibitor concentration

K i :

Inhibitor concentration required to achieve half maximum inhibition

Km :

Michaelis Menten constant

Km apparent :

Km of the reaction in the presence of an inhibitor

Mϕ :

Macrophages

MDR :

Multidrug-resistant

MH agar :

Mueller Hinton Agar

MMOXC :

4-Methoxy,1-methyl-2-oxo-pyridine,3-carbomide

MOI :

Multiplicities of infection

MRSA :

Methicillin resistant Staphylococcus aureus

MSCRAMMs :

Microbial surface components recognizing adhesive matrix molecules

Mur-F :

UDP-N-acetyl muramyl pentapeptide ligase

MTT :

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

NOS :

Nitric oxide synthase

LB media :

Luria Bertini media

PDF :

Peptidyl deformylase

RAW 264.7 :

Ralph and William’s cell line 264.7

RNS :

Reactive nitrogen species

ROS :

Reactive oxygen species

SOD :

Superoxide dismutase

THP-1 cell line :

Human monocytic cell line

UMPK :

Uridine monophosphate kinase

UMT :

UDP-N-acetyl muramic acid tripeptide

PBS :

Phosphate-buffered saline

PCR :

Polymerase chain reaction

PMA :

Phorbol 12-myristate 13-acetate

RPMI :

Roswell Park Memorial Institute

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Acknowledgements

We sincerely acknowledge the Sri Venkateswara Institute of Medical Sciences and University for providing facilities to carry out this work. This work forms part of the PhD work to be submitted to SVIMS University.

Funding

This work was supported by a Sri Balaji Arogya Vara Prasadini (SBAVP) scheme (Grant No. SBAVP/PhD/28 dated: 30th December 2019).

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Authors and Affiliations

  1. Microbial Genetics Laboratory, Department of Biotechnology, Sri Venkateswara Institute of Medical Sciences and University, Alipiri Road, Andhra Pradesh, 517501, Tirupati, India

    Subbarayudu Suthi, Deepika Gopi & Potukuchi Venkata Gurunadha Krishna Sarma

  2. Department of Microbiology, Sri Venkateswara Institute of Medical Sciences, Tirupati, 517501, Andhra Pradesh, India

    Abhijit Chaudhary

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Contributions

PVGK conceived the idea and design of the experiments; SSR was involved in the development and optimization of experimental methods; DPK participated in the microbial experiments; SSR and PVGK participated in the analysis and interpretation of data; PVGK, SSR, and ACH worked together to prepare the manuscript and revised the manuscript.

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Correspondence to Potukuchi Venkata Gurunadha Krishna Sarma.

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Suthi, S., Gopi, D., Chaudhary, A. et al. The Therapeutic Potential of 4-Methoxy-1-methyl-2-oxopyridine-3-carbamide (MMOXC) Derived from Ricinine on Macrophage Cell Lines Infected with Methicillin-Resistant Strains of Staphylococcus aureus. Appl Biochem Biotechnol 195, 2843–2862 (2023). https://doi.org/10.1007/s12010-022-04269-w

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