Tigecycline is one of the last-resort antibiotics to treat complicated infections caused by both multidrug-resistant (MDR) Gram-negative and Gram-positive bacteria 1 . Tigecycline resistance has sporadically occurred in recent years, primarily due to chromosome-encoding mechanisms, such as overexpression of efflux pumps and ribosome protection 2 , 3 . Here we report the emergence of plasmid-mediated mobile tigecycline resistance mechanism Tet(X4) in Escherichia coli isolates from China, which is capable of degrading all tetracyclines, including tigecycline and the FDA newly approved eravacycline. The tet (X4)-harboring IncQ1 plasmid is highly transferable, and can be successfully mobilized and stabilized in recipient clinical and laboratory strains of Enterobacteriaceae bacteria. It is noteworthy that tet (X4)-positive E. coli strains, including isolates co-harboring mcr-1 , have been widely detected in pigs, chickens, soil, and dust samples in China. In vivo murine models demonstrated that the presence of Tet(X4) led to tigecycline treatment failure. Consequently, the emergence of plasmid-mediated Tet(X4) challenges the clinical efficacy of the entire family of tetracycline antibiotics. Importantly, our study raises concern that the plasmid-mediated tigecycline resistance may further spread into a variety of ecological niches and into clinical high-risk pathogens. Collective efforts are in urgent need to preserve the potency of these essential antibiotics.
The chemical diversity of physiological DNA modifications has expanded with the identification of phosphorothioate (PT) modification in which the nonbridging oxygen in the sugar-phosphate backbone of DNA is replaced by sulfur. Together with DndFGH as cognate restriction enzymes, DNA PT modification, which is catalyzed by the DndABCDE proteins, functions as a bacterial restriction-modification (R-M) system that protects cells against invading foreign DNA. However, the occurrence of systems across a large number of bacterial genomes and their functions other than R-M are poorly understood. Here, a genomic survey revealed the prevalence of bacterial systems: 1,349 bacterial systems were observed to occur sporadically across diverse phylogenetic groups, and nearly half of these occur in the form of a solitary gene cluster that lacks the restriction counterparts. A phylogenetic analysis of 734 complete PT R-M pairs revealed the coevolution of M and R components, despite the observation that several PT R-M pairs appeared to be assembled from M and R parts acquired from distantly related organisms. Concurrent epigenomic analysis, transcriptome analysis, and metabolome characterization showed that a solitary PT modification contributed to the overall cellular redox state, the loss of which perturbed the cellular redox balance and induced to reconfigure its metabolism to fend off oxidative stress. An in vitro transcriptional assay revealed altered transcriptional efficiency in the presence of PT DNA modification, implicating its function in epigenetic regulation. These data suggest the versatility of PT in addition to its involvement in R-M protection.
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.
The major objective was to measure the trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid) equivalent antioxidant capacity (TEAC) of carbazole derivatives (Ar 2 NHs) by means of scavenging 2,2 0 -diphenyl-1-picrylhydrazyl (DPPH) and the 2,2 0 -azinobis(3-ethylbenzothiazoline-6-sulfonate) radical cation (ABTS +Á ). The Ar 2 NHs included phenoxazine (PozNH), phenothiazine (PtzNH), iminostilbene (IsbNH) and diphenylamine (DpaNH), and the TEAC of trolox, a-tocopherol (TocH), L-ascorbic acid (VC) and L-ascorbyl-6-laurate (VC-12) were measured as well. The TEAC results revealed that the ability to scavenge DPPH (PozNH [ IsbNH *PtzNH * TroH *TocH *VC *VC12), differed from the ability to scavenge ABTS + (PtzNH [ IsbNH [ PozNH [ DpaNH * TroH *TocH *VC *VC12). CazNH did not react with DPPH and ABTS +Á . Furthermore, the addition of acetic acid accelerated the reaction rate of Ar 2 NH to scavenge DPPH, suggesting that a sequential proton loss electron transfer (SPLET) mechanism occurred with amine-type antioxidants during the trapping of DPPH. In contrast, the addition of acetic acid or pyridine reduced the reaction rate of Ar 2 NH to scavenge ABTS +. , suggesting that the hydrogen atom transfer (HAT) mechanism is the basis for the reaction that is occurring.
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