SummaryWidespread resistance to first-line TB drugs is a major problem that will likely only be resolved through the development of new drugs with novel mechanisms of action. We have used structure-guided methods to develop a lead molecule that targets the thioesterase activity of polyketide synthase Pks13, an essential enzyme that forms mycolic acids, required for the cell wall of Mycobacterium tuberculosis. Our lead, TAM16, is a benzofuran class inhibitor of Pks13 with highly potent in vitro bactericidal activity against drug-susceptible and drug-resistant clinical isolates of M. tuberculosis. In multiple mouse models of TB infection, TAM16 showed in vivo efficacy equal to the first-line TB drug isoniazid, both as a monotherapy and in combination therapy with rifampicin. TAM16 has excellent pharmacological and safety profiles, and the frequency of resistance for TAM16 is ∼100-fold lower than INH, suggesting that it can be developed as a new antitubercular aimed at the acute infection.PaperClip

N-Boc- and N-ethoxycarbonyl-4-pyridones and the resulting 2,3-dihydropyridones undergo 1,4-addition reactions with Grignard reagents in the presence of chlorotrimethylsilane (TMSCl) or BF3·Et2O in excellent yields. Copper catalysis is not required, and mechanistic considerations suggest that the reaction is proceeding by a conjugate addition pathway rather than by a pathway involving 1,2-addition to an intermediate pyridinium ion. TMSCl-mediated conjugate addition of Grignard reagents to 2-substituted-2,3-dihydropyridones gives the trans-2,6-disubstitued piperidinones stereoselectively, while cuprate reagents give either the trans or cis diastereomers or mixtures.

Food safety concerns associated with products purchased at farmers' markets have arisen, highlighting the growing need for farmers' market consumer and producer awareness of potential public health issues. The focus of this quantitative research study was to assess the prevalence and antimicrobial resistance of foodborne pathogens in select value-added commodities (i.e., animal treats, soil amendments, herbs, honey, dressings, exotic foods, etc.) randomly procured from farmers' markets in Central Virginia. Between March and November 2017, collection of 194 samples originating from 40 individual farmers' market vendors selling at 11 different farmers' markets transpired. Detection of potentially harmful bacterial species within collected samples was as follows: 0.5% Campylobacter, 24.5% Escherichia coli, 16.7% Listeria, and 1.0% Salmonella. Bacterial isolates (n = 155) of Campylobacter, E. coli, Listeria, and Salmonella were tested for their susceptibility to 12 antimicrobials. Tetracycline and ampicillin resistance showed the highest frequency among E. coli (approximately 30%) isolates. Nalidixic acid resistance was the highest in Listeria isolates (79.4%). Approximately 17% of E. coli isolates and more than 50% of each Campylobacter, Listeria, and Salmonella isolates exhibited multidrug resistance (MDR). No E. coli isolates had matching pulsed-field gel electrophoresis profiles demonstrating that the isolates had a high degree of genomic diversity and farm specificity. This study demonstrated an emerging public health threat of the presence of MDR arising from farmers' market-acquired value-added commodities. The importance of this research study highlights the value of implementing good agricultural and handling practices from farm (producer vendors) to table (consumers) to avert potential foodborne illness occurrence. Future research to determine potential reasons and supply chain interventions for the observed prevalence of MDR bacterial isolates from farmers' market value-added products is paramount.Disclaimer: This study simply indicates the occurrence and multidrug resistance (MDR) of foodborne pathogens on various and randomly selected value-added commodities available at farmers' markets in Virginia. Due to the limited availability of same commodities at different vendors among farmers' markets, each commodity acquired in duplicate may not be representative of all value-added commodities in the study area. However, the findings are noteworthy to understand the prevalence and MDR of foodborne pathogens on those commodities available at farmers' markets in broad spectrum. The authors would like to declare that this study was carried out, mainly for academic research purpose without any conflict of interest. Furthermore, mention of trade names or commercial products in this publication is solely for the purpose of providing specific information and does not imply recommendation or endorsement by Virginia State University.

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Aflatoxin, produced by Aspergillus flavus, is hazardous to health of humans and livestock. The lack of information about large effect QTL for resistance to aflatoxin accumulation is a major obstacle to employ marker-assisted selection for maize improvement. The understanding of resistance mechanisms of the host plant and the associated genes is necessary for improving resistance to A. flavus infection. A suppression subtraction hybridization (SSH) cDNA library was made using the developing kernels of Mp715 (resistant inbred) and B73 (susceptible inbred) and 480 randomly selected cDNA clones were sequenced to identify differentially expressed genes (DEGs) in response to A. flavus infection and map these clones onto the corn genome by in-silico mapping. A total of 267 unigenes were identified and majority of genes were related to metabolism, stress response, and disease resistance. Based on the reverse northern hybridization experiment, 26 DEGs were selected for semi-quantitative RT-PCR analysis in seven inbreds with variable resistance to aflatoxin accumulation at two time points after A. flavus inoculation. Most of these genes were highly expressed in resistant inbreds. Quantitative RT-PCR analysis validated upregulation of PR-4, DEAD-box RNA helicase, and leucine rich repeat family protein in resistant inbreds. Fifty-six unigenes, which were placed on linkage map through in-silico mapping, overlapped the QTL regions for resistance to aflatoxin accumulation identified in a mapping population derived from the cross between B73 and Mp715. Since majority of these mapped genes were related to disease resistance, stress response, and metabolism, these should be ideal candidates to investigate host pathogen interaction and to reduce aflatoxin accumulation in maize.