As a complex multicellular structure of the vascular system at the central nervous system (CNS), the blood-brain barrier (BBB) separates the CNS from the system circulation and regulates the influx and efflux of substances to maintain the steady-state environment of the CNS. Lipopolysaccharide (LPS), the cell wall component of Gram-negative bacteria, can damage the barrier function of BBB and further promote the occurrence and development of sepsis-associated encephalopathy (SAE). Here, we conduct a literature review of the direct and indirect damage mechanisms of LPS to BBB and the relationship between these processes and SAE. We believe that after LPS destroys BBB, a large number of inflammatory factors and neurotoxins will enter and damage the brain tissue, which will activate brain immune cells to mediate inflammatory response and in turn further destroys BBB. This vicious circle will ultimately lead to the progression of SAE. Finally, we present a succinct overview of the treatment of SAE by restoring the BBB barrier function and summarize novel opportunities in controlling the progression of SAE by targeting the BBB.

The emergence and spread of mobilized colistin resistance (mcr) genes have triggered extensive concerns worldwide. Here, we characterized the global distribution of mcr-9, a newly-identified variant of mcr, by assembling the data set of mcr-9-positive isolates from GenBank database and the literature available. Genetic features of all the mcr-9-harboring plasmids were determined by bioinformatic analysis. We showed that mcr-9 is globally distributed in 21 countries across six continents, with a wide dissemination among various species of Enterobacteriaceae strains from human, animal, food and environment. IncHI2-ST1 plasmids were found to be the predominant replicon type carrying mcr-9. Comparative genomics highlighted that IncHI2-type plasmids may also serve as a critical reservoir of mcr-9, from which different types of circulating plasmids acquired the mcr-9. Results revealed that the rcnR-rcnA-pcoE-pcoS-IS903-mcr-9-wbuC structure was consistent in most mcr-9 cassettes, suggesting a relatively unitary model involved in the mobilization of mcr-9. It is most likely that the spread of mcr-9 was mainly attributed to the conjugation and recombination events of mcr-9-carrying plasmids. In summary, our results provide a comprehensive picture of the distribution and genetic environment of mcr-9, and demonstrate the central roles played by IncHI2 plasmids in the worldwide dissemination of mcr-9.

Hospital sewage plays a key role in the dissemination of antibiotic-resistant genes (ARGs) by serving as an environmental antimicrobial resistance reservoir. In this study, we aimed to characterize the cephalosporin- and carbapenem-resistant isolates from hospital sewage and receiving rivers. The results showed that ESBL (bla_CTX-M) and carbapenemase genes (bla_NDM and bla_KPC) were widely detected in a number of different bacterial species. These resistance genes were mainly harbored in Enterobacteriaceae, followed by Acinetobacter and Aeromonas isolates. More attention should be given to these bacteria as important vectors of ARGs in the environment. Furthermore, we showed that the multidrug resistance phenotype was highly prevalent, which was found in 85.5% Enterobacteriaceae and 75% Acinetobacter strains. Notably, the presence of carbapenemase genes in isolates from treated effluents and receiving rivers indicates that the discharges of wastewater treatment plants could be an important source for high-risk resistance genes propagation to the environment. In conclusion, this study shows a high prevalence of ESBL- and carbapenemase-producing bacteria in hospital sewage and receiving rivers in China. These findings have serious implications for human health, and also suggest the need for more efforts to control the dissemination of resistant bacteria from hospital sewage into the environment.

Background: Colistin acts as the last line of defense against severe infections caused by carbapenem-resistant Enterobacteriaceae. Infections caused by extensively drug-resistant isolates coproducing MCR and carbapenemases have posed a serious public health concern. Purpose: In this study, we reported the first clinical colistin and carbapenem-resistant Enterobacter hormaechei isolate SCNJ07 coharboring bla_NDM-1 and mcr-9 from a patient with bloodstream infection in China. Methods: Bacterial antimicrobial susceptibility testing was performed using the broth microdilution method. Conjugation assay was carried out to investigate the transferability of mcr-9 and bla_NDM-1. Whole-genome sequencing of strain SCNJ07 was performed using an Illumina HiSeq system and the genetic characteristics of the mcr-9- and bla_NDM-1-harboring plasmids were analyzed. Results: Conjugation assays revealed that both bla_NDM-1 and mcr-9 genes could successfully transfer their resistance phenotype to Escherichia coli strain J53. Whole genome sequencing showed that SCNJ07 possessed an FIB36:FIIY4 type self-transmissible plasmid bearing bla_NDM-1, which possessed high similarity to previously reported pRJF866 in China. mcr-9 was located on a ∼28-kb self-transmissible plasmid pMCR-SCNJ07 with both IncHI2 and IncR replicons. Two copies of intact IS903 that bracketed a ∼8-kb region containing the mcr-9 gene were identified in pMCR-SCNJ07. BLASTn analysis revealed that a number of mcr-9-positive plasmids have been around for a while among Enterobacteriaceae worldwide. Conclusion: This study reveals the likelihood of a wide dissemination of this newly identified colistin resistance gene mcr-9 among Enterobacteriaceae. Further surveillance is urgently needed to understand the prevalence and dissemination of mcr-9, thereby facilitating establishment of measures to control its spread.

A carbapenem-resistant hypermucoviscous Klebsiella pneumoniae isolate was recovered from human sputum. Whole genome sequencing of this isolate was carried out to reveal its clonal background, antimicrobial resistance determinants and virulence factors. Virulence assays were performed using wax moth larvae. The transfer of blaNDM-5 between bacterial strains was tested using conjugation. 59 genome assemblies of ST29 K. pneumoniae and 230 IncX3 plasmids regardless of the carriage of resistance gene were employed for phylogenetic analysis, respectively. The strain carried a virulence plasmid pVir-SCNJ1 bearing the virulence gene rmpA and exhibited a high virulence in wax moth. This hypervirulent strain belongs to sequence type 29 and carries blaNDM-5, which is located on a conjugative plasmid, designated pNDM5-SCNJ1, belonging to type IncX3. pNDM5-SCNJ1 was fully sequenced and shows high similarity with pNDM_MGR194, except some deletion inside the ISAba125 region. Phylogenetic analysis of IncX3 plasmids revealed that although blaNDM-5 can be evolved from blaNDM-1 via point mutations within some IncX3 plasmids, most of blaNDM-5-carrying IncX3 plasmids probably have acquired blaNDM-5 in multiple events. In this study, we characterized a blaNDM-5-positive hypervirulent K. pneumoniae of sequence type 29 in China. Our results highlight the need for active surveillance on this lineage of carbapenem-resistant K. pneumoniae.

The emergence of carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKP) has driven us to explore alternative treatments for the limitation of antimicrobial agents. Lytic phages are considered a promising alternative treatment for CR-hvKP infection. In this study, we reported three novel lytic phages, vB_KpnA_SCNJ1-Z, vB_KpnS_SCNJ1-C, and vB_KpnM_SCNJ1-Y, against a CR-hvKP strain SCNJ1, and they possess genomes of double-stranded DNA with a size of 43,428 bp, 46,039 bp, and 50,360 bp, respectively. Phylogenetic analysis demonstrated that vB_KpnA_SCNJ1-Z belongs to the family Autographiviridae within the class Caudoviricetes, while vB_KpnS_SCNJ1-C and vB_KpnM_SCNJ1-Y are unclassified Caudoviricetes. The phages showed a narrow host range only lysing 1 of 50 tested clinical bacterial strains. The one-step growth curves and stability results showed that the phages displayed relatively short latency periods, with broad pH (pH 3-14) and thermal stabilities (20–60°C). The phages showed significant inhibition of the biofilm formation by SCNJ1 and strong antibacterial activity in vitro. In the mouse model, we demonstrated that administration of a single phage or phage cocktail significantly reduced bacteria loads in the lung, liver, and spleen, and effectively rescued mice from the infection of the SCNJ1 strain, with a survival rate of 70-80%. These findings suggested the three phages have great potential as an alternative therapy with favorable stability and strong antibacterial activity both in vivo and in vitro for the treatment of CR-hvKP infection.