Evaluation of a Dual-Acting Antibacterial Agent, TNP-2092, on Gut Microbiota and Potential Application in the Treatment of Gastrointestinal and Liver Disorders.

Abstract

TNP-2092 is a unique multitargeting drug conjugate with extremely low propensity for development of resistance. The in vitro activity of TNP-2092 against a panel of urease-producing bacteria was similar to that of rifaximin, a locally acting antibiotic approved for the treatment of hepatic encephalopathy, irritable bowel syndrome with diarrhea, and traveler's diarrhea. When given orally, TNP-2092 exhibited low absorption and the majority of compound was recovered in feces as parent. The impact of oral TNP-2092 on gut microbiota was investigated in rats. TNP-2092 was administered to rats by oral gavage for 7 days. Feces samples were collected and analyzed by 16S rRNA sequencing. Although the total amount of bacterial load appeared relatively unchanged before, during, and after treatment, significant changes in the relative abundance of certain gut bacteria at family and genus levels were observed. Some of the changes are known to be associated with improvement of symptoms associated with liver cirrhosis and hepatic encephalopathy. The observed effects of TNP-2092 on gut microbiota in rats were similar to those of rifaximin. In vivo, TNP-2092 demonstrated potent efficacy in a mouse Clostridium difficile infection model, superior to metronidazole and vancomycin, with no relapse observed after treatment. TNP-2092 is currently in clinical development for the treatment of symptoms associated with gastrointestinal and liver disorders.