Kathayat, D. | Search bioRxiv

bioRxiv2026

Discovery and Structure Activity Relationship Optimization of a Novel Rv1625c Agonist Chemotype with Antitubercular Activity

Rv1625c/Cya has emerged as a promising target for the development of treatment-shortening therapies for tuberculosis. Screening of an Enamine compound library identified sBQQ004 as an initial hit, and rapid hit optimization led to compound 1, which was subsequently confirmed as an Rv1625c/Cya agonist. Structure activity relationship studies identified lead compound 25 with potent activity against Mycobacterium tuberculosis H37Rv under cholesterol-dependent growth conditions (MIC = 0.27 uM) and strong intramacrophage activity (EC50 = 0.079 uM). Compounds 1 and 25 showed oral bioavailabilities of 84.5% and 51.9% in mice, respectively. Repeat BID dosing of compound 1 resulted in a dose- and time-dependent decrease in systemic exposure. Despite this pharmacokinetic limitation, the potency and overall profile of this chemotype encouraged continued optimization.

microbiology↗

bioRxiv2019

Nasal and gut microbiota for sows of different health status within six commercial swine farms from one swine production system

Sow culling is an essential practice in swine herds to optimize animal health and productivity; and cull sows represent a considerable proportion of the herd at any given time point. Even though recent studies have reported that the microbiome is associated with susceptibility to diseases, the microbiome in the cull sow population has not been explored. The main objective of this study was to investigate whether there were differences in abundance and diversity of microbes encountered in the gut and upper respiratory tract of sows of different health status (healthy, cull, and compromised cull sows) and different farms. Farms were visited once, 30 individual fecal and nasal swab samples were obtained per farm; and pooled across animals by health status and farm in pools of five. Genomic DNA was extracted and samples were subjected to MiSeq 16S rRNA sequencing using Illumina MiSeq. Diversity analyses were conducted using QIIME. Alpha diversity was analyzed using observed OTUs, PD Whole Tree, and Chao1; and beta diversity was assessed using weighted UniFrac. The mean number of OTUs was 3,846.97{+/-}9,078.87 and 28,747.92{+/-}14,090.50 for nasal and fecal pooled samples, respectively. Diversity of the nasal microbiota was low compared to the gut microbiota. For nasal samples, there was a difference in diversity between samples from farms 1-6 using the Chao1 metric (p = 0.0005); and weighted beta diversity values indicated clustering by health status. For fecal samples, there was no difference in diversity between compromised, cull, and healthy sows; or between samples from farms 1-6. Weighted PCoA analyses showed an influence of farm of origin on the diversity of pooled fecal samples. Finally, differences at the genus level were found in the fecal microbiota composition of sows of different health status and farm of origin; but not for nasal microbiota.

epidemiology↗