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© The Author(s) 2020., Anthropogenic environments have been implicated in enrichment and exchange of antibiotic resistance genes and bacteria. Here we study the impact of confined and controlled swine farm environments on temporal changes in the gut microbiome and resistome of veterinary students with occupational exposure for 3 months. By analyzing 16S rRNA and whole metagenome shotgun sequencing data in tandem with culture-based methods, we show that farm exposure shapes the gut microbiome of students, resulting in enrichment of potentially pathogenic taxa and antimicrobial resistance genes. Comparison of students’ gut microbiomes and resistomes to farm workers’ and environmental samples revealed extensive sharing of resistance genes and bacteria following exposure and after three months of their visit. Notably, antibiotic resistance genes were found in similar genetic contexts in student samples and farm environmental samples. Dynamic Bayesian network modeling predicted that the observed changes partially reverse over a 4-6 month period. Our results indicate that acute changes in a human’s living environment can persistently shape their gut microbiota and antibiotic resistome., This work was jointly supported by the National Key Research and Development Program of China (2016YFD0501300 to Y.-H.L.), the Program for Changjiang Scholars and Innovative Research Team in University of Ministry of Education of China (IRT_17R39 to Y.-H.L.), the Foundation for Innovation and Strengthening School Project of Guangdong (2016KCXTD010 to Y.-H.L.), the National Natural Science Foundation of China (31730097 to Y.-H.L.), the 111 Project (D20008 to J.S., X.-P.L., and Y.-H.L.), the Institutional Program Unifying Population and Laboratory-Based Sciences Burroughs Wellcome Fund grant to Washington University (supporting A.W.D.), and the National Institutes of Health (NIH) Director’s New Innovator Award (to G.D.).

The antibacterial efficacy of valnemulin against Staphylococcus aureus was studied ex vivo in broiler chickens after intravenous and intramuscular administration at a dose of 10 mg/kg bodyweight (BW). The minimum inhibitory concentrations (MICs) of valnemulin against S. aureus strains ATCC 25923 in broth and serum were 0.12 and 1 µg/mL, respectively. The MIC50 and MIC90 of valnemulin against all susceptible S. aureus strains isolated from chickens in the test population were 0.06 and 0.12 μg/mL, respectively. Protein binding, which greatly influences the efficacy of valnemulin, was assayed by equilibrium dialysate in vitro. A high binding fraction of 86.2% was found, which seems in good agreement with the difference of bacterial susceptibility tests observed in broth and serum. The surrogate index of AUC0–24/MIC required for the lowest bacteriostatic effect, and 2 log10CFU reduction in bacterial count were 24.4 h and 38.0 h, respectively. The required daily dose of valnemulin for a bacteriostatic activity was calculated to be 15 mg/kg BW based on the MIC90 of 0.12 µg/mL. Considering the slow disposition process of valnemulin and an AUC0–24 h value of more than 10-fold obtained from diseased animals, a suggested dose of 3 mg/kg BW is sufficient to achieve a satisfactory therapeutic efficacy in infected broilers. Due to the time-dependent antibacterial characteristics of valnemulin, the recommended daily dose should be split into two or three sub-doses to achieve the highest effectiveness while diminishing the risk of development of bacterial resistance.

Infections with influenza A viruses are still a major threat to humans and several animal species. The occurrence of highly pathogenic avian influenza viruses capable of infecting and killing humans highlights the urgency for a new and efficient strategy for the treatment of diseases caused by the virus. Andrographolide and its derivatives have been widely used for treating respiratory infections in China for decades. We have recently synthesized new andrographolide derivatives and found that some of the compounds including 14-alpha-lipoyl andrographolide (AL-1) have significant activity against bacterial infections with an unique mechanism of action. We report here the antiviral activity of AL-1 and other andrographolide drugs. AL-1 showed significant activity against influenza A viruses including the H5N1 avian influenza virus. The administration of AL-1 by oral gavage to mice infected with avian influenza A/Chicken/Guangdong /96 (H9N2), A/Duck/Guangdong/99 (H5N1), and human influenza A/PR/8/34 (H1N1) viruses greatly reduced the death rate, prolonged life, inhibited lung consolidation, and reduced viral titers in the lung. The most effective dosage of AL-1 in these studies ranged from 100 to 200 mg/kg/d, when administered twice daily for 7 d beginning 24 h before viral exposure. The LD(50) of AL-1 was 1243 mg/kg/d. AL-1 was effective against avian influenza A (H9N2 and H5N1) and human influenza A H1N1 viruses in vitro, with the 50% effective concentrations ranging from 7.2 to 15.2 microM and the selective indexes ranging from 51 to 109. Significant inhibition of viral adsorption onto red blood cells with minimum inhibitory concentrations ranging from 5.3 to 16.8 mM suggested that AL-1 was capable of directly interfering with viral hemagglutinin to block binding to cellular receptors. With potent antiviral activity and a potentially new mechanism of action, AL-1 may warrant further evaluation as a possible therapy for influenza.