Objective:To investigate the expression of c-Src in cholangiocarcinoma (CCA) and its relationship with clinical pathological features.Methods:The bile duct tissue of 68 CCA patients who underwent surgical resection at the Lhasa People′s Hospital from January 2017 to December 2022 and the normal bile duct tissue of 18 patients with common bile duct stones were selected. The expression of c-Src in bile duct tissue was detected using SP immunohistochemistry, and the expression of c-Src in CCA and its relationship with clinical pathological features were analyzed.Results:The positive rate of c-Src in CCA tissue was 58.82%(40/68), significantly higher than the 16.67%(3/18, P<0.01) in normal bile duct tissue. The expression score of c-Src in CCA tissues with metastasis was significantly higher than that in CCA tissues without metastasis ( P<0.01). Conclusions:The expression of c-Src is significantly increased in CCA tissues, and the expression of c-Src is also significantly increased in CCA tissues with metastasis, indicating that c-Src promotes the invasion and metastasis of CCA.

The bacterial ATP-competitive GyrB/ParE subunits of type II topoisomerase are important anti-bacterial targets to treat super drug-resistant bacterial infections. Herein we 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novel pyrrolamide-type GyrB/ParE inhibitors based on the structural modifications of the candidate AZD5099 that was withdrawn from the clinical trials due to safety liabilities such as mitochondrial toxicity.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.