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Antibacterial properties of 3-(phenylsulfonyl)-2-pyrazinecarbonitrile

Journal Article


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Abstract


  • The emergence of multidrug-resistant bacterial strains has heightened the need for new antimicrobial agents based on novel chemical scaffolds that are able to circumvent current modes of resistance. We recently developed a whole-animal drug-screening methodology in pursuit of this goal and now report the discovery of 3-(phenylsulfonyl)-2-pyrazinecarbonitrile (PSPC) as a novel antibacterial effective against resistant nosocomial pathogens. The minimum inhibitory concentrations (MIC) of PSPC against Staphylococcus aureus and Enterococcus faecium were 4 μg/mL and 8 μg/mL, respectively, whereas the MICs were higher against the Gram-negative bacteria Klebsiella pneumoniae (64 μg/mL), Acinetobacter baumannii (32 μg/mL), Pseudomonas aeruginosa (>64 μg/mL), and Enterobacter spp. (>64 μg/mL). However, co-treatment of PSPC with the efflux pump inhibitor phenylalanine arginyl β-naphthylamide (PAβN) or with sub-inhibitory concentrations of the lipopeptide antibiotic polymyxin B reduced the MICs of PSPC against the Gram-negative strains by >4-fold. A sulfide analog of PSPC (PSPC-1S) showed no antibacterial activity, whereas the sulfoxide analog (PSPC-6S) showed identical activity as PSPC across all strains, confirming structure-dependent activity for PSPC and suggesting a target-based mechanism of action. PSPC displayed dose dependent toxicity to both Caenorhabditis elegans and HEK-293 mammalian cells, culminating with a survival rate of 16% (100 μg/mL) and 8.5% (64 μg/mL), respectively, at the maximum tested concentration. However, PSPC did not result in hemolysis of erythrocytes, even at a concentration of 64 μg/mL. Together these results support PSPC as a new chemotype suitable for further development of new antibiotics against Gram-positive and Gram-negative bacteria.

Authors


  •   Rajamuthiah, Rajmohan (external author)
  •   Jayamani, Elamparithi (external author)
  •   Majed, Hiwa (external author)
  •   Conery, Annie L. (external author)
  •   Kim, Wooseong (external author)
  •   Kwon, Bumsup (external author)
  •   Fuchs, Beth (external author)
  •   Kelso, Michael J.
  •   Ausubel, Frederik M. (external author)
  •   Mylonakis, Eleftherios (external author)

Publication Date


  • 2015

Citation


  • Rajamuthiah, R., Jayamani, E., Majed, H., Conery, A. L., Kim, W., Kwon, B., Fuchs, B. Burgwyn., Kelso, M. J., Ausubel, F. M. & Mylonakis, E. (2015). Antibacterial properties of 3-(phenylsulfonyl)-2-pyrazinecarbonitrile. Bioorganic and Medicinal Chemistry Letters, 25 (22), 5203-5207.

Scopus Eid


  • 2-s2.0-84945936961

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=4333&context=smhpapers

Ro Metadata Url


  • http://ro.uow.edu.au/smhpapers/3310

Has Global Citation Frequency


Number Of Pages


  • 4

Start Page


  • 5203

End Page


  • 5207

Volume


  • 25

Issue


  • 22

Place Of Publication


  • United Kingdom

Abstract


  • The emergence of multidrug-resistant bacterial strains has heightened the need for new antimicrobial agents based on novel chemical scaffolds that are able to circumvent current modes of resistance. We recently developed a whole-animal drug-screening methodology in pursuit of this goal and now report the discovery of 3-(phenylsulfonyl)-2-pyrazinecarbonitrile (PSPC) as a novel antibacterial effective against resistant nosocomial pathogens. The minimum inhibitory concentrations (MIC) of PSPC against Staphylococcus aureus and Enterococcus faecium were 4 μg/mL and 8 μg/mL, respectively, whereas the MICs were higher against the Gram-negative bacteria Klebsiella pneumoniae (64 μg/mL), Acinetobacter baumannii (32 μg/mL), Pseudomonas aeruginosa (>64 μg/mL), and Enterobacter spp. (>64 μg/mL). However, co-treatment of PSPC with the efflux pump inhibitor phenylalanine arginyl β-naphthylamide (PAβN) or with sub-inhibitory concentrations of the lipopeptide antibiotic polymyxin B reduced the MICs of PSPC against the Gram-negative strains by >4-fold. A sulfide analog of PSPC (PSPC-1S) showed no antibacterial activity, whereas the sulfoxide analog (PSPC-6S) showed identical activity as PSPC across all strains, confirming structure-dependent activity for PSPC and suggesting a target-based mechanism of action. PSPC displayed dose dependent toxicity to both Caenorhabditis elegans and HEK-293 mammalian cells, culminating with a survival rate of 16% (100 μg/mL) and 8.5% (64 μg/mL), respectively, at the maximum tested concentration. However, PSPC did not result in hemolysis of erythrocytes, even at a concentration of 64 μg/mL. Together these results support PSPC as a new chemotype suitable for further development of new antibiotics against Gram-positive and Gram-negative bacteria.

Authors


  •   Rajamuthiah, Rajmohan (external author)
  •   Jayamani, Elamparithi (external author)
  •   Majed, Hiwa (external author)
  •   Conery, Annie L. (external author)
  •   Kim, Wooseong (external author)
  •   Kwon, Bumsup (external author)
  •   Fuchs, Beth (external author)
  •   Kelso, Michael J.
  •   Ausubel, Frederik M. (external author)
  •   Mylonakis, Eleftherios (external author)

Publication Date


  • 2015

Citation


  • Rajamuthiah, R., Jayamani, E., Majed, H., Conery, A. L., Kim, W., Kwon, B., Fuchs, B. Burgwyn., Kelso, M. J., Ausubel, F. M. & Mylonakis, E. (2015). Antibacterial properties of 3-(phenylsulfonyl)-2-pyrazinecarbonitrile. Bioorganic and Medicinal Chemistry Letters, 25 (22), 5203-5207.

Scopus Eid


  • 2-s2.0-84945936961

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=4333&context=smhpapers

Ro Metadata Url


  • http://ro.uow.edu.au/smhpapers/3310

Has Global Citation Frequency


Number Of Pages


  • 4

Start Page


  • 5203

End Page


  • 5207

Volume


  • 25

Issue


  • 22

Place Of Publication


  • United Kingdom