Deglycosylated Azithromycin Targets Transgelin to Enhance Intestinal Smooth Muscle Function

Weilong Zhong; Bo Sun; Hao Ruan; Guang Yang; Baoxin Qian; Hailong Cao; Lingfei He; Yunjing Fan; Arthur G Roberts; Xiang Liu; Xuejiao Hu; Yuan Liang; Qing Ye; Tingting Yin; Bangmao Wang; Cheng Yang; Tao Sun; Honggang Zhou

doi:10.1016/j.isci.2020.101464

Deglycosylated Azithromycin Targets Transgelin to Enhance Intestinal Smooth Muscle Function

iScience. 2020 Aug 14;23(9):101464. doi: 10.1016/j.isci.2020.101464. eCollection 2020 Sep 25.

Authors

Weilong Zhong^{1

2}, Bo Sun², Hao Ruan³, Guang Yang³, Baoxin Qian⁴, Hailong Cao^{1

2}, Lingfei He³, Yunjing Fan³, Arthur G Roberts⁵, Xiang Liu¹, Xuejiao Hu³, Yuan Liang³, Qing Ye⁴, Tingting Yin³, Bangmao Wang¹, Cheng Yang^{3

2}, Tao Sun^{3

2}, Honggang Zhou^{3

2}

Affiliations

¹ Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Disease, Tianjin 300052, China.
² Tianjin Key Laboratory of Early Druggability Evaluation of Innovative Drugs and Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin 300450, China.
³ State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin 300350, China.
⁴ Department of Gastroenterology and Hepatology, Tianjin Key Laboratory of Artificial Cells, Tianjin Institute of Hepatobiliary Disease, Tianjin Third Central Hospital, Tianjin 300041, China.
⁵ Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, GA 30602, USA.

Abstract

Azithromycin (AZM) has been widely used as an antibacterial drug for many years. It has also been used to treat delayed gastric emptying. However, it exerts several side effects. We found that deglycosylated AZM (Deg-AZM or CP0119), an AZM metabolite, is a positively strong intestinal agonist that may result in the intestinal mobility experienced by patients after AZM administration. We confirmed that Deg-AZM can function strongly on intestinal peristalsis and identified transgelin as its potential molecular target. Furthermore, our pharmacological studies showed that the binding of Deg-AZM to transgelin enhanced the contractility of intestinal smooth muscle cells by facilitating the assembly of actin filaments into tight bundles and stress fibers. Specifically, Deg-AZM promoted intestinal peristaltic activity in wild-type mice but not in transgelin (-/-) mice. Moreover, Deg-AZM did not exert antibacterial activity and did not disrupt intestinal flora. Thus, Deg-AZM may become a potential drug for slow-transit constipation treatment.

Keywords: Drugs; Medical Biochemistry; Molecular Biology.