Antimicrobial and Efflux Pump Inhibitory Activity of Carvotacetones from Sphaeranthus africanus Against Mycobacteria

doi:10.3390/antibiotics9070390

. 2020 Jul 8;9(7):390.

doi: 10.3390/antibiotics9070390.

Antimicrobial and Efflux Pump Inhibitory Activity of Carvotacetones from Sphaeranthus africanus Against Mycobacteria

Huyen Thi Tran^{1

2}, Julia Solnier^{1

3}, Eva-Maria Pferschy-Wenzig¹, Olaf Kunert⁴, Liam Martin³, Sanjib Bhakta³, Loi Huynh⁵, Tri Minh Le², Rudolf Bauer¹, Franz Bucar¹

Affiliations

¹ Institute of Pharmaceutical Sciences, Department of Pharmacognosy, University of Graz, Universitaetsplatz 4, 8010 Graz, Austria.
² School of Medicine, Vietnam National University-HCMC, Quarter 6, Linh Trung Ward, Thu Duc District, HCM City 700000, Vietnam.
³ Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck, University of London, Malet Street, London WC1E 7HX, UK.
⁴ Institute of Pharmaceutical Sciences, Department of Pharmaceutical Chemistry, University of Graz, Schubertstraße 1, 8010 Graz, Austria.
⁵ Department of Pharmacognosy, School of Medicine and Pharmacy, Da Nang University, 41 Le Duan Street, Hai Chau District, Da Nang City 550000, Vietnam.

PMID: 32650510
PMCID: PMC7400215
DOI: 10.3390/antibiotics9070390

Antimicrobial and Efflux Pump Inhibitory Activity of Carvotacetones from Sphaeranthus africanus Against Mycobacteria

Huyen Thi Tran et al. Antibiotics (Basel). 2020.

. 2020 Jul 8;9(7):390.

doi: 10.3390/antibiotics9070390.

Authors

Huyen Thi Tran^{1

2}, Julia Solnier^{1

3}, Eva-Maria Pferschy-Wenzig¹, Olaf Kunert⁴, Liam Martin³, Sanjib Bhakta³, Loi Huynh⁵, Tri Minh Le², Rudolf Bauer¹, Franz Bucar¹

Affiliations

¹ Institute of Pharmaceutical Sciences, Department of Pharmacognosy, University of Graz, Universitaetsplatz 4, 8010 Graz, Austria.
² School of Medicine, Vietnam National University-HCMC, Quarter 6, Linh Trung Ward, Thu Duc District, HCM City 700000, Vietnam.
³ Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck, University of London, Malet Street, London WC1E 7HX, UK.
⁴ Institute of Pharmaceutical Sciences, Department of Pharmaceutical Chemistry, University of Graz, Schubertstraße 1, 8010 Graz, Austria.
⁵ Department of Pharmacognosy, School of Medicine and Pharmacy, Da Nang University, 41 Le Duan Street, Hai Chau District, Da Nang City 550000, Vietnam.

PMID: 32650510
PMCID: PMC7400215
DOI: 10.3390/antibiotics9070390

Abstract

Carvotacetones (1-7) isolated from Sphaeranthus africanus were screened for their antimycobacterial and efflux pump (EP) inhibitory potential against the mycobacterial model strains Mycobacterium smegmatis mc² 155, Mycobacterium aurum ATCC 23366, and Mycobacterium bovis BCG ATCC 35734. The minimum inhibitory concentrations (MICs) of the carvotacetones were detected through high-throughput spot culture growth inhibition (HT-SPOTi) and microbroth dilution assays. In order to assess the potential of the compounds 1 and 6 to accumulate ethidium bromide (EtBr) in M. smegmatis and M. aurum, a microtiter plate-based fluorometric assay was used to determine efflux activity. Compounds 1 and 6 were analyzed for their modulating effects on the MIC of EtBr and the antibiotic rifampicin (RIF) against M. smegmatis. Carvotacetones 1 and 6 had potent antibacterial effects on M. aurum and M. bovis BCG (MIC ≤ 31.25 mg/L) and could successfully enhance EtBr activity against M. smegmatis. Compound 1 appeared as the most efficient agent for impairing the efflux mechanism in M. smegmatis. Both compounds 1 and 6 were highly effective against M. aurum and M. bovis BCG. In particular, compound 1 was identified as a valuable candidate for inhibiting mycobacterial efflux mechanisms and as a promising adjuvant in the therapy of tuberculosis or other non-tubercular mycobacterial infections.

Keywords: Compositae; Sphaeranthus africanus L.; carvotacetones; efflux pump inhibitors; efflux pumps; ethidium bromide accumulation; mycobacteria.

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Conflict of interest statement

The authors declare no conflicts of interest. The funders had no role in the design of the study, in the collection, analyses, or interpretation of data, in the writing of the manuscript, or in the decision to publish the results.

Figures

**Figure 1**
Chemical structures of compounds **1–7** isolated from *Sphaeranthus africanus* [21,22].

**Figure 2**
The increase of EtBr accumulation in M. *smegmatis* mc² 155 (a) and *M. aurum* ATCC 23366 (b) generated by concentrations MIC/2 of the potential efflux pump inhibitors (EPIs) 1 and 6 and the reference inhibitors, verapamil (VP) and chlorpromazine (CPZ), included as two positive controls. EtBr, the negative control, was tested at 0.5 mg/L. The curves represent means ± standard deviations (SD); n = 3.

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[1] Baker S.J., Payne D.J., Rappuoli R., De Gregorio E. Technologies to address antimicrobial resistance. Proc. Natl. Acad. Sci. USA. 2018;115:12887–12895. doi: 10.1073/pnas.1717160115. - DOI - PMC - PubMed

[2] Baker S.J., Payne D.J., Rappuoli R., De Gregorio E. Technologies to address antimicrobial resistance. Proc. Natl. Acad. Sci. USA. 2018;115:12887–12895. doi: 10.1073/pnas.1717160115. - DOI - PMC - PubMed

[3] Aslam B., Wang W., Arshad M.I., Khurshid M., Muzammil S., Rasool M.H., Nisar M.A., Alvi R.F., Aslam M.A., Qamar M.U. Antibiotic resistance: A rundown of a global crisis. Infect. Drug Resist. 2018;11:1645. doi: 10.2147/IDR.S173867. - DOI - PMC - PubMed

[4] Aslam B., Wang W., Arshad M.I., Khurshid M., Muzammil S., Rasool M.H., Nisar M.A., Alvi R.F., Aslam M.A., Qamar M.U. Antibiotic resistance: A rundown of a global crisis. Infect. Drug Resist. 2018;11:1645. doi: 10.2147/IDR.S173867. - DOI - PMC - PubMed

[5] Tacconelli E., Carrara E., Savoldi A., Harbarth S., Mendelson M., Monnet D.L., Pulcini C., Kahlmeter G., Kluytmans J., Carmeli Y. Discovery, research, and development of new antibiotics: The WHO priority list of antibiotic-resistant bacteria and tuberculosis. Lancet Infect. Dis. 2018;18:318–327. doi: 10.1016/S1473-3099(17)30753-3. - DOI - PubMed

[6] Tacconelli E., Carrara E., Savoldi A., Harbarth S., Mendelson M., Monnet D.L., Pulcini C., Kahlmeter G., Kluytmans J., Carmeli Y. Discovery, research, and development of new antibiotics: The WHO priority list of antibiotic-resistant bacteria and tuberculosis. Lancet Infect. Dis. 2018;18:318–327. doi: 10.1016/S1473-3099(17)30753-3. - DOI - PubMed

[7] Solnier J., Martin L., Bhakta S., Bucar F. Flavonoids as novel efflux pump inhibitors and antimicrobials against both environmental and pathogenic intracellular mycobacterial species. Molecules. 2020;25:734. doi: 10.3390/molecules25030734. - DOI - PMC - PubMed

[8] Solnier J., Martin L., Bhakta S., Bucar F. Flavonoids as novel efflux pump inhibitors and antimicrobials against both environmental and pathogenic intracellular mycobacterial species. Molecules. 2020;25:734. doi: 10.3390/molecules25030734. - DOI - PMC - PubMed

[9] Fair R.J., Tor Y. Antibiotics and bacterial resistance in the 21st century. Perspect. Med. Chem. 2014;6:PMC.S14459. doi: 10.4137/PMC.S14459. - DOI - PMC - PubMed

[10] Fair R.J., Tor Y. Antibiotics and bacterial resistance in the 21st century. Perspect. Med. Chem. 2014;6:PMC.S14459. doi: 10.4137/PMC.S14459. - DOI - PMC - PubMed

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Antimicrobial and Efflux Pump Inhibitory Activity of Carvotacetones from Sphaeranthus africanus Against Mycobacteria

Affiliations

Antimicrobial and Efflux Pump Inhibitory Activity of Carvotacetones from Sphaeranthus africanus Against Mycobacteria

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Affiliations

Abstract

Conflict of interest statement

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