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

作者：Rajamuthiah Rajmohan; Jayamani Elamparithi; Majed Hiwa; Conery Annie L; Kim Wooseong; Kwon Bumsup; Fuchs Beth Burgwyn; Kelso Michael J; Ausubel Frederick M; Mylonakis Eleftherios^*

来源：Bioorganic & Medicinal Chemistry Letters, 2015, 25(22): 5203-5207.

DOI：10.1016/j.bmcl.2015.09.066

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

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 mu g/mL and 8 mu g/mL, respectively, whereas the MICs were higher against the Gram-negative bacteria Klebsiella pneumoniae (64 mu g/mL), Acinetobacter baumannii (32 mu g/mL), Pseudomonas aeruginosa (>64 mu g/mL), and Enterobacter spp. (>64 mu g/mL). However, co-treatment of PSPC with the efflux pump inhibitor phenylalanine arginyl beta-naphthylamide (PA beta N) 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 mu g/mL) and 8.5% (64 mu g/mL), respectively, at the maximum tested concentration. However, PSPC did not result in hemolysis of erythrocytes, even at a concentration of 64 mu g/mL. Together these results support PSPC as a new chemotype suitable for further development of new antibiotics against Gram-positive and Gram-negative bacteria.

• 出版日期2015-11-15