ZLN005 improves the survival of polymicrobial sepsis by increasing the bacterial killing via inducing lysosomal acidification and biogenesis in phagocytes

Abstract

Polymicrobial sepsis still has a high mortality rate despite the development of antimicrobial agents, elaborate strategies to protect major organs, and the investment of numerous medical resources. Mitochondrial dysfunction, which acts as the center of energy metabolism, is clearly the basis of pathogenesis. Drugs that act on PGC1α, the master regulator of mitochondrial biosynthesis, have shown useful effects in the treatment of sepsis; therefore, we investigated the efficacy of ZLN005, a PGC1α agonist, and found significant improvement in overall survival in an animal model. The mode of action of this effect was examined, and it was shown that the respiratory capacity of mitochondria was enhanced immediately after administration and that the function of TFEB, a transcriptional regulator that promotes lysosome biosynthesis and mutually enhances PGC1α, was enhanced, as was the physical contact between mitochondria and lysosomes. ZLN005 strongly supported immune defense in early sepsis by increasing lysosome volume and acidity and enhancing cargo degradation, resulting in a significant reduction in bacterial load. ZLN005 rapidly acted on two organelles, mitochondria and lysosomes, against sepsis and interactively linked the two to improve the pathogenesis. This is the first demonstration that acidification of lysosomes by a small molecule is a mechanism of action in the therapeutic strategy for sepsis, which will have a significant impact on future drug discovery.

Peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family in physiological and pathophysiological process and diseases

“…The hurdle of expanding their clinical indications by targeting PGC-1α involves toxicology analyses, dosing, and formulation optimization. In addition, PGC-1α activator ZLN005 and inhibitor SR-18292 have been developed and applied in animal experiments, 19,509,577,[737][738][739] However, gaps and differences exist between rodent models and humans, thus more clinical trials are required.…”

Host-directed therapy for bacterial infections -Modulation of the phagolysosome pathway-

“…ZLN005 was originally recognized as a peroxisome proliferator-activated receptor gamma coactivator 1-a (PGC1a) activator (203). By administering ZLN005 to the cecum perforation ligation (CPL) model of sepsis and analyzing intraperitoneal cells, ZLN005 was shown to be a transcription factor EB (TFEB) activator involved in lysosome biogenesis as well as a lysosomal acidifier (204). The compound significantly improved overall survival and drastically reduced intraperitoneal bacterial load in mice at only 2 h after administration of ZLN005 in in vivo sepsis model.…”