Andrographolide and 4-Phenylbutyric Acid Administration Increase the Expression of Antimicrobial Peptides Beta-Defensin-1 and Cathelicidin and Reduce Mortality in Murine Sepsis

Abstract

Antibiotic resistance is a global threat and requires the search for new treatment strategies. Natural antimicrobial peptides (AMPs) have pronounced antibacterial, antiviral, antifungal, and antitumor activity. AMPs’ clinical use is complicated by the high synthesis costs and rapid proteolytic degradation. The search for small molecules, inducers of endogenous AMP expression, could become a new approach. Here, we investigated for the first time the effect of seven small molecules (andrographolide, levofloxacin, azithromycin, montelukast, 4-phenylbutyric acid, rosuvastatin and valsartan) on AMP (beta-defensin-1, hBD-1 and cathelicidin, LL-37) serum levels in rats. In control groups, the level of hBD-1 was 295.0 (292.9–315.4) pg/mL, and for LL-37, it was 223.8 (213.3–233.6) pg/mL. Andrographolide (ANDR) and 4-phenylbutyric acid (4-PHBA) administration significantly enhanced the level of both AMPs. The hBD-1 level was 581.5 (476.3–607.7) pg/mL for ANDR and 436.9 (399.0–531.6) pg/mL for 4-PHBA. The LL-37 level was 415.4 (376.2–453.8) pg/mL for ANDR and 398.9 (355.7–410.1) pg/mL for 4-PHBA. Moreover, we have shown that these compounds reduce mortality in a murine model of sepsis caused by a carbapenem-resistant Klebsiella aerogenes isolate. From our point of view, these small molecules are promising candidates for further study as potent AMP inducers. The data obtained allow the development of new strategies to combat antibiotic resistance and infectious diseases.

Keywords

• antimicrobial peptide
• antibiotic resistance
• andrographolide
• 4-phenylbutyric acid
• defensin
• cathelicidin