ABSTRACT
MraY (phospho-N-acetylmuramoyl-pentapeptide-transferase) inhibitory natural products are attractive molecules as candidates for a new class of antibacterial agents to combat antimicrobial-resistant bacteria. Structural optimization of these natural products is required to improve their drug-like properties for therapeutic use. However, chemical modifications of these natural products are painstaking tasks due to complex synthetic processes, which is a bottleneck in advancing natural products to the clinic. Here, we develop a strategy for a comprehensive in situ evaluation of the build-up library, which enables us to streamline the preparation of the analogue library and directly assess its biological activities. We apply this approach to a series of MraY inhibitory natural products. Through construction and evaluation of the 686-compound library, we identify promising analogues that exhibit potent and broad-spectrum antibacterial activity against highly drug-resistant strains in vitro as well as in vivo in an acute thigh infection model. Structures of the MraY-analogue complexes reveal distinct interaction patterns, suggesting that these analogues represent MraY inhibitors with unique binding modes. We further demonstrate the generality of our strategy by applying it to tubulin-binding natural products to modulate their tubulin polymerization activities.
Subject(s)
Anti-Bacterial Agents , Bacterial Proteins , Biological Products , Microbial Sensitivity Tests , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/chemical synthesis , Biological Products/pharmacology , Biological Products/chemistry , Bacterial Proteins/antagonists & inhibitors , Bacterial Proteins/metabolism , Animals , Mice , Humans , Transferases (Other Substituted Phosphate Groups)ABSTRACT
SCOPE: Diallyl trisulfide (DATS), an organosulfur compound generates in crushed garlic, has various beneficial health effects. A growing body of evidence indicates that miRNAs are involved in the pathology of lifestyle diseases including obesity. The anti-obesogenic effect of garlic is previously reported; however, the effects of DATS on obesity, and the relationship between garlic compounds and the involvement of miRNA remains unclear. Here, the anti-obesogenic activity of DATS and the potential role of miRNA in a diet-induced obesity rat model are investigated. METHODS AND RESULTS: Oral administration of DATS suppressed body and white adipose tissue (WAT) weight gain in rats fed a high-fat diet compared with vehicle-administered rats. DATS lowered the plasma and liver triglyceride levels in obese rats, and decreased lipogenic mRNA levels including those of Srebp1c, Fasn, and Scd1 in the liver. DATS also suppressed de novo lipogenesis in the liver. Transcriptomic analyses of miRNA and mRNA in the epididymal WAT of obese rats using microarrays revealed that DATS decreased miRNA-335 expression and normalized the obesity-related mRNA transcriptomic signatures in epididymal WAT. CONCLUSION: The potent anti-obesogenic effects of DATS and its possible mechanism of action was clearly demonstrated in this study.
