Design, synthesis, and antibacterial activity of 2-benzylidiene-3- oxobutanmide derivatives against resistant pathogens Ankur Sood, Prof. V Kesavan Indian Institute of Technology (IIT), Madras, Chennai, India Resistance to antibiotics develops naturally because of random mutation. Misuse and overuse of antibiotics accelerate the above process, and led to the emergence of multi-drug resistance pathogens especially in microbes 1 . Among the bacteria, ESKAPE ( Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species ) bacteria are a significant cause of multidrug-resistant infections, and new drugs are urgently needed to combat these pathogens. 2 Very few new antibiotic classes have successfully developed since the "golden age" discovery of penicillin and flurry of other's antibiotics in the 1950s and 1960s. Since then, the number of FDA approved antibiotics have declined, and those approved are predominantly active against gram-positive bacteria 3,4 . It inspired us to identify a new small molecule which is expected to possess broad-spectrum antibacterial activity (i.e. which inhibit/kill the growth of both gram- positive and gram-negative bacteria). Development of new chemical entities which are effective against resistant bacteria is a formidable challenge. In this work, novel 2-benzylidene-3-oxobutanamide and its analogs were synthesized. Seven analogs exhibited mild to high antibacterial activity against WHO priority drug-resistant pathogens such as Acinetobacter baumannii (ATCC 19606) and Staphylococcus aureus MRSA (ATCC 43300) . Time kill assay experiments revealed that these molecules are bactericidal against gram-negative bacteria and bacteriostatic against gram-positive bacteria. Moreover, in cultured human embryonic kidney cells (HEK) and hemolysis assay, potent compounds showed minimal toxicity. These finding suggest that these small molecules with excellent antibacterial activity have potential to combat antibacterial resistance. Also, this results indicate that these molecules have the potential to become an active pharmaceutical ingredient (API) as a broad-spectrum antibacterial drug in the future. References 1. X. Luo, L. Qian, Y. Xiao, Y. Tang, Y. Zhao, X. Wang, L. Gu, Z. Lei, J. Bao, J. Wu, T. He, F. Hu, J. Zheng, H. Li, W. Zhu, L. Shao, X. Dong, D. Chen, X. Qian and Y. Yang, Nature Communications , 2019, 10, 1-12. 2. M. Sprenger, Journal of Global Antimicrobial Resistance , 2019, 18, 305-308. 3. World Health Organization‎. Prioritization of pathogens to guide discovery, research and development of new antibiotics for drug-resistant bacterial infections, including tuberculosis, 2017. World Health Organization. https://apps.who.int/iris/ handle/10665/311820. (accessed 9/01/2022, 2022) 4. R. J. Fair, and Y. Tor, Perspectives in medicinal chemistry, 2014, 6, 25-64.
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