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

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posted on 2024-11-14, 23:34 authored by Rajmohan Rajamuthiah, Elamparithi Jayamani, Hiwa Majed, Annie L Conery, Wooseong Kim, Bumsup Kwon, Beth Fuchs, Michael Kelso, Frederik M Ausubel, Eleftherios Mylonakis
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.

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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.

Journal title

Bioorganic and Medicinal Chemistry Letters

Volume

25

Issue

22

Pagination

5203-5207

Language

English

RIS ID

103885

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