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

Rajmohan Rajamuthiah, Elamparithi Jayamani, Hiwa Majed, Annie L. Conery, Wooseong Kim, Bumsup Kwon, Beth Burgwyn Fuchs, Michael J. Kelso, Frederick M. Ausubel, Eleftherios Mylonakis

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)5203-5207
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Issue number22
StatePublished - Nov 15 2015


  • C. elegans
  • Efflux pump inhibition
  • High throughput screening
  • Liquid infection assay
  • MRSA
  • Staphylococcus aureus
  • Synergism

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry


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