https://doi.org/10.1016/j.apsb.2023.08.030
This new article publication from Acta Pharmaceutica Sinica B, discusses discovery and druggability evaluation of pyrrolamide-type GyrB/ParE inhibitor against drug-resistant bacterial infection.
The bacterial ATP-competitive GyrB/ParE subunits of type II topoisomerase are important anti-bacterial targets to treat super drug-resistant bacterial infections. The authors of this article discovered novel pyrrolamide-type GyrB/ParE inhibitors based on the structural modifications of the candidate AZD5099 that was withdrawn from the clinical trials due to safety liabilities such as mitochondrial toxicity.
The hydroxyisopropyl pyridazine compound 28 had a significant inhibitory effect on Gyrase (GyrB, IC50 = 49 nmol/L) and a modest inhibitory effect on Topo IV (ParE, IC50 = 1.513 μmol/L) of Staphylococcus aureus. It also had significant antibacterial activities on susceptible and resistant Gram-positive bacteria with a minimum inhibitory concentration (MIC) of less than 0.03 μg/mL, which showed a time-dependent bactericidal effect and low frequencies of spontaneous resistance against S. aureus. Compound 28 had better protective effects than the positive control drugs such as DS-2969 (5) and AZD5099 (6) in mouse models of sepsis induced by methicillin-resistant Staphylococcus aureus (MRSA) infection. It also showed better bactericidal activities than clinically used vancomycin in the mouse thigh MRSA infection models. Moreover, compound 28 has much lower mitochondrial toxicity than AZD5099 (6) as well as excellent therapeutic indexes and pharmacokinetic properties.
At present, compound 28 has been evaluated as a pre-clinical drug candidate for the treatment of drug-resistant Gram-positive bacterial infection. On the other hand, compound 28 also has good inhibitory activities against stubborn Gram-negative bacteria such as Escherichia coli (MIC = 1 μg/mL), which is comparable with the most potent pyrrolamide-type GyrB/ParE inhibitors reported recently. In addition, the structure–activity relationships of the compounds were also studied.
Keywords: GyrB/ParE inhibitor, Anti-bacterial infection, Structural modifications, Druggability evaluation
Graphical Abstract: available at https://ars.els-cdn.com/content/image/1-s2.0-S2211383523003374-ga1_lrg.jpg
A novel pyrrolamide-type GyrB/ParE inhibitor against drug-resistant bacterial infection with excellent pharmacological activity and druggability was discovered by the structural modifications of the AZD5099 which was withdrawn from clinical trials.
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The Journal of the Institute of Materia Medica, the Chinese Academy of Medical Sciences and the Chinese Pharmaceutical Association.
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CiteScore: 19.4
Impact Factor: 14.5
JIF without self-citation: 13.7
ISSN 2211-3835
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Xintong Zhao, Jing Feng, Jie Zhang, Zunsheng Han, Yuhua Hu, Hui-Hui Shao, Tianlei Li, Jie Xia, Kangfan Lei, Weiping Wang, Fangfang Lai, Yuan Lin, Bo Liu, Kun Zhang, Chi Zhang, Qingyun Yang, Xinyu Luo, Hanyilan Zhang, Chuang Li, Wenxuan Zhang, Song Wu, Discovery and druggability evaluation of pyrrolamide-type GyrB/ParE inhibitor against drug-resistant bacterial infection,
Acta Pharmaceutica Sinica B, Volume 13, Issue 12, 2023, Pages 4945-4962, ISSN 2211-3835, https://doi.org/10.1016/j.apsb.2023.08.030