PCSK9 inhibitors and osteoporosis: mendelian randomization and meta-analysis.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors represent an effective strategy for reducing cardiovascular disease risk. Yet, PCSK9's impact on osteoporosis remains unclear. Hence, we employed Mendelian randomization (MR) analysis for examining PCSK9 inhibitor effects on osteoporosis. METHODS: Single nucleotide polymorphisms (SNPs) for 3-hydroxy-3-methylglutaryl cofactor A reductase (HMGCR) and PCSK9 were gathered from available online databases for European pedigrees. Four osteoporosis-related genome-wide association studies (GWAS) data served as the main outcomes, and coronary artery disease (CAD) as a positive control for drug-targeted MR analyses. The results of MR analyses examined by sensitivity analyses were incorporated into a meta-analysis for examining causality between PCSK9 and HMGCR inhibitors and osteoporosis. RESULTS: The meta-analysis involving a total of 1,263,102 subjects, showed that PCSK9 inhibitors can increase osteoporosis risk (P < 0.05, I2, 39%). However, HMGCR inhibitors are not associated with osteoporosis risk. Additionally, a replication of the analysis was conducted with another exposure-related GWAS dataset, which led to similar conclusions. CONCLUSION: PCSK9 inhibitors increase osteoporosis risk. However, HMGCR inhibitors are unremarkably linked to osteoporosis.

Genetically predicted triglycerides mediate the relationship between type 2 diabetes Mellitus and intervertebral disc degeneration.

BACKGROUND: To validate the causal relationship between type 2 diabetes mellitus (T2DM) and intervertebral disc degeneration (IVDD) and to identify and quantify the role of triglycerides (TGs) as potential mediators. METHODS: A two-sample Mendelian randomization (MR) analyses of T2DM (61,714 cases and 1178 controls) and IVDD (20,001 cases and 164,682 controls) was performed using genome-wide association studies (GWAS). Moreover, two-step MR was employed to quantify the proportionate impact of TG-mediated T2DM on IVDD. RESULTS: MR analysis showed that T2DM increased IVDD risk (OR: 1.0466, 95% CI 1.0049-1.0899, P = 0.0278). Reverse MR analyses demonstrated that IVDD does not affect T2DM risk (P = 0.1393). The proportion of T2DM mediated through TG was 11.4% (95% CI 5.5%-17.4%). CONCLUSION: This work further validates the causality between T2DM and IVDD, with a part of the effect mediated by TG, but the greatest impacts of T2DM on IVDD remain unknown. Further studies are needed to identify other potential mediators.

Emerging resistance mechanisms for 4 types of common anti-MRSA antibiotics in Staphylococcus aureus: A comprehensive review.

Staphylococcus aureus is one of the leading hospital-associated and community-associated pathogens, which has caused a global public health concern. The emergence of methicillin-resistant S. aureus (MRSA) along with the widespread use of different classes of antibiotics has become a significant therapeutic challenge. Antibiotic resistance is a disturbing problem that poses a threat to humans. Treatment options for S. aureus resistant to ß-lactam antibiotics include glycopeptide antibiotic, cyclic lipopeptide antibiotic, cephalosporins and oxazolidinone antibiotic. The most representative types of these antibiotics are vancomycin, daptomycin, ceftaroline and linezolid. The frequent use of the first-line drug vancomycin for MRSA treatment has increased the number of resistant strains, namely vancomycin intermediate resistant S. aureus (VISA) and vancomycin resistant S. aureus (VRSA). A systematic literature review of relevant published studies in PubMed before 2020 was conducted. In recent years, there have been some reports on the relevant resistant mechanisms of vancomycin, daptomycin, ceftaroline and linezolid. In this review, we have summarized the antibiotic molecular modes of action and different gene mutants at the whole-genome level, which will aid in further development on new drugs for effective MRSA treatment based on describing different resistance mechanisms of classic antibiotics.

Analysis on the virulomes and resistomes of multi-drug resistance clinical Escherichia coli isolates, as well as the interactome with gut microbiome.

Escherichia coli is one of the most diverse microbial species. Pathogenic E. coli is capable of causing various diseases in humans, including several types of diarrhea, urinary tract infections, sepsis, and meningitis. This study focused on the antibiotic susceptibility profile and genomic analysis of a clinical E. coli Guangzhou-Eco330 isolated from a hospitalized 8-year-old female patient suffered from pulmonary infection in 2017. Susceptibility to 15 antibiotics were determined using Vitek2™ Automated Susceptibility System and Etest strips and interpreted based on CLSI guidelines. The genome was sequenced using Illumina Hiseq 2500 platform and assembled de novo using Velvet, followed by bioinformatics analysis. The genome has a length of 5,132,642 bp and contains 4989 predicted genes with an average GC content of 50.51%. The carriage of rfbE gene suggested the strain belonging to O157. In the genome, 70 non-coding RNAs, 50 repeat sequences, 18 transposons, 78 GIs, 9 CRISPRs, and 3 large prophages were identified. 37 PHI related genes and 108 virulence genes were determined to contribute to its pathogenicity. Specifically, the acquisition of multiple antibiotic resistance genes including blaCTX-M-55, blaOXA-10, blaCMY-48, tetB, and qnrS1 contributed to its resistance to penicillins, telracyclines, cephalosporin, and quinolones. The understanding of the genome may aid in further study on the clinical control of multi-drug resistance E. coli.

Prevalence of qnrVC Genes in Pseudomonas aeruginosa Clinical Isolates from Guangdong, China.

Pseudomonas aeruginosa is a serious nosocomial pathogen with high morbidity and mortality due to the increasing resistance to antibiotics in recent years. qnrVC genes have been proven as a source of antibiotic resistance, but relationship with Pseudomonas aeruginosa remains not clear. We aimed to investigate the prevalence and molecular characteristics of qnrVC genes in P. aeruginosa clinical isolates. A total of 874 nonduplicate clinical isolates were collected in Guangdong, China, between January 2011 and June 2015. The presence of qnrVC genes and their genotypes were determined using PCR amplification and DNA sequencing. Antibiotic susceptibilities were tested, and the genetic relatedness of qnrVC-positive isolates were analyzed by multi-locus sequence typing (MLST) and pulsed field gel electrophoresis (PFGE). Consequently, we found 2.3% of P. aeruginosa isolates were present with qnrVC genes, displaying more resistant to various antibiotics. Phylogenetic analysis of qnrVC-positive strains revealed that antibacterial resistance among qnrVC-positive P. aeruginosa isolates in Guangdong probably emerged from multiple sources and was not spread by clonal strains.

Transcriptome Analysis of Two Strains of Proteus mirabilis with Swarming Migration Deficiency Isolated from Patients with Urinary Tract Infection.

Two rare strains of Proteus mirabilis with swarming migration deficiency were isolated from urine samples of two patients with urinary tract infections and were named as G121 and G137. Migration experiments showed that P. mirabilis HI4320 had typical migration on blood agar, while G121 and G137 had significantly weakened migration ability. Results of adhesion tests showed that the adhesion ability of G121 and G137 to the bladder epithelial cell line 5637 was significantly reduced. High-throughput sequencing and alignment analysis of the transcriptomes of the three P. mirabilis strains were conducted, with P. mirabilis HI4320 as the reference strain. Reverse transcription quantitative PCR (RT-qPCR) was used to verify differentially expressed genes. Results of transcriptome analysis and RT-qPCR showed that, compared to the HI4320 strain, genes related to flagellum and fimbria formation, dicarboxylate transport, and cystathionine and anthranilate metabolism were down-regulated in G121 and G137, while genes related to iron transport, molybdenum metabolism, and metalloprotease were up-regulated, suggesting that these genes may be involved in the migration ability and epithelial cell adhesion ability of P. mirabilis. These results provide important insight to the search for virulence genes and the screening of new antibacterial targets for P. mirabilis.

Emergence and genomic analysis of MDR Laribacter hongkongensis strain HLGZ1 from Guangzhou, China.

Background: Laribacter hongkongensis is a facultative anaerobic, non-fermentative, Gram-negative bacillus associated with community-acquired gastroenteritis and traveller's diarrhoea. No clinical MDR L. hongkongensis isolate has been reported yet. Methods: We performed WGS (PacBio and Illumina) on a clinical L. hongkongensis strain HLGZ1 with an MDR phenotype. Results: HLGZ1 was resistant to eight classes of commonly used antibiotics. Its complete genome was a single circular chromosome of 3 424 272 bp with a G + C content of 62.29%. In comparison with the reference strain HLHK9, HLGZ1 had a higher abundance of genes associated with DNA metabolism and recombination. Several inserts including two acquired resistance gene clusters (RC1 and RC2) were also identified. RC1 carried two resistance gene cassette arrays, aac(6')-Ib-cr-aadA2-Δqac-Δsul1-floR-tetR-tetG and arr-3-dfrA32-ereA2-Δqac-sul1, which shared significant nucleotide sequence identities with the MDR region of Salmonella Genomic Island 1 from Salmonella enterica serovar Typhimurium DT104. There was also an integron-like structure, intl1-arr3-dfrA27-Δqac-sul1-aph(3')-Ic, and a tetR-tetA operon located on RC2. MLST analysis identified HLGZ1 as ST167, a novel ST clustered with two strains previously isolated from frogs. Conclusions: This study provides insight into the genomic characteristics of MDR L. hongkongensis and highlights the possibilities of horizontal resistance gene transfer in this bacterium with other pathogens.

Integron mediated bacterial resistance and virulence on clinical pathogens.

Integron was recognized as mobile elements responsible for the emergence and diffusion of antibiotic resistance, virulence and pathogenicity. The existence of resistant integron in pathogens may consequently lead to the increasing number of clinical failures in bacterial mediated diseases, as well as the expenses. In this study, a total of 22 clinical pathogens (including E. faecalis, S. aureus, K. pneumoniae, Enterobacter, P. aeruginosa and Acinetobacter) were subjected to the identification of class 1-class 3 integrons and drug resistant gene cassettes by high flux LAMP method. According to the results, the clinical isolates were screened as carrying class 1 integron with dfrA12-orfF-aadA2 cassette array, class 1 integron with dfrA17-aadA5 cassette array, class 1 integron with aadA2 cassette, class 1 integron with blaVIM2 cassette, class 1 and class 2 integron with dfrA1-sat1-aadA1 and dfrA12-orfF-aadA2 cassette arrays simultaneously, which was accordantly with the previous data. The optimized high flux LAMP assay was proceeded in water bath at 65 °C for 60 min and determined by naked eye, with the time consumption restricted within 2.5 h. Prior to conventional PCR method, the high flux LAMP assay was demonstrated as a highly-specific and highly-sensitive method. This study offered a valid LAMP method in resistance integrons detection for laboratory use, which was time-saving and easy-determination.

Emergence and Plasmid Analysis of Klebsiella pneumoniae KP01 Carrying blaGES-5 from Guangzhou, China.

Klebsiella pneumoniae strain KP01 carrying blaGES-5 was identified from a patient in Guangzhou, China. High-throughput sequencing assigned blaGES-5 to a 28.5-kb nonconjugative plasmid, pGES-GZ. A 13-kb plasmid backbone sequence on pGES-GZ was found to share high sequence identities with plasmids from Gram-negative nonfermenters. A novel class 1 integron carrying a gene cassette array of orf28-orf28-blaGES-5 was identified on pGES-GZ, within which orf28 encoded a hypothetical protein possibly correlated to fosfomycin resistance.

resistome analysis of Enterobacter cloacae CY01, an extensively drug-resistant strain producing VIM-1 metallo-ß-lactamase from China.

Resistome analysis of clinical VIM-1-producing Enterobacter cloacae strain CY01 from China revealed the presence of multiple resistance determinants. Two resistance plasmids were identified in CY01. The pCY-VIM plasmid was 14 kb in size and possessed a replicase gene (repA), a gene cluster encoding the partitioning function (parABC), and a carbapenemase gene (blaVIM-1). Another 5.9-kb plasmid, pCY-MdT, with an aac(6')-Ib gene, was very closely related (13 nucleotide differences) to pMdT1, a ColE1 plasmid carrying aac(6')-Ib-cr4.

Therapeutic potential of single-nucleotide polymorphism-mediated IL6R inhibitors in ankylosing spondylitis treatment.

Objective: Interleukin-6 (IL-6) is a multiple-effect cell factor implicated in the etiopathogenesis of several rheumatologic disorders. The blockade of the IL-6 pathway via IL6R inhibitors effectively treats these disorders. However, the clinical significance of the IL6R blockade for ankylosing spondylitis (AS) therapy remains controversial. With advances in genomics, increasing evidence has revealed the role of heritability in the etiology of disease, and Mendelian randomization (MR) analyses are being used more broadly to infer causation. Therefore, this MR study aims to evaluate the potential therapeutic utility of IL6R-targeted approaches in AS. Methods: The C-reactive protein (CRP) level was used as an exposure factor, and rheumatoid arthritis (RA) was used as a positive control. As-related genome-wide association study (GWAS) data were used as the primary outcome of drug-targeted MR analyses to test the relation between IL6R blockers and AS. Inverse variance weighting (IVW) is the primary analytical approach. Various sensitivity tests were performed to check the robustness and trustworthiness of the causality estimation, including consistency, heterogeneity, and pleiotropy analyses. In addition, repeated analysis was conducted using different GWAS data related to exposures and outcomes to examine the results for stability. Results: According to the IVW results, IL6R inhibitors significantly reduced the risk of AS in ukb-b-18194 (OR: 0.995, 95% CI 0.993-0.996, P = 5.12 × 10-08) and ukb-a-88 (OR: 0.994, 95% CI 0.993-0.996, P = 6.25 × 10-15). Moreover, repeated analyses were performed using different exposure-related GWAS data, yielding similar results, ukb-b-18194 (OR: 0.995, 95% CI 0.993-0.997, P = 1.25 × 10-06) and ukb-a-88 (OR: 0.995, 95% CI 0.994-0.997, P = 7.81 × 10-09). Heterogeneity analyses and pleiotropy analyses indicated no significant heterogeneity or pleiotropy. Conclusion: This MR analysis result further validates that the IL-6 pathway may contribute to the pathogenesis of AS and that the inhibition of IL6R reduces the risk of AS. These findings may guide future studies and provide more favorable drug treatment options for people at high risk of AS.

Discovering Potential Mechanisms of Intervertebral Disc Disease Using Systematic Mendelian Randomization of Human Circulating Immunocytomics.

BACKGROUND: Although intervertebral disc degeneration (IVDD) is a critical factor in many spine-related diseases and has an extremely high prevalence in the aging population, the potential pathogenesis remains to be clarified entirely. Immune cells have been found to perform an essential function during the onset and progression of IVDD in recent years. Therefore, we explored the association between immune cell characteristics and IVDD through Mendelian randomization (MR) analysis and further delved into the mediating role of potential metabolites. METHODS: Based on the MR analysis, the association of 731 immune cell phenotypes and 1400 metabolites on IVDD were assessed. Single nucleotide polymorphisms were closely associated the expression levels of immune cell characteristics and the concentrations of metabolites and have been used as instrumental variables for deducing them as risk factors or protective factors for IVDD. In addition, mediation analyses have been performed to identify potential metabolite mediators between immune cell characteristics and IVDD. RESULTS: MR analysis identified 27 immune cell phenotypes and 79 metabolites significantly associated with IVDD. In addition, mediation analysis was performed by selecting the immune cell phenotype that most significantly increased the risk of IVDD - CD86 on monocytes. A total of 4 metabolite-mediated mediation relationships were revealed (3 b-hydroxy-5-cholenoic acid, X-22509, N-acetyl-L-glutamine, and N2-acetyl, N6, N6-dimethyllysine). CONCLUSIONS: The findings of this analysis identified underlying association between immune cell phenotypes, metabolite, and IVDD that may serve as predictive and prognostic clinical biomarkers and benefit IVDD pathogenesis research.

Global emergence of double and multi-carbapenemase producing organisms: epidemiology, clinical significance, and evolutionary benefits on antimicrobial resistance and virulence.

Redundant carbapenemase-producing (RCP) bacteria, which carry double or multiple carbapenemases, represent a new and concerning phenomenon. The objective of this study is to conduct a comprehensive analysis of the epidemiology and genetic mechanisms of RCP strains to support targeted surveillance and control measures. A retrospective analysis was conducted using surveillance data from 277 articles. Statistical analysis was performed to determine and evaluate species prevalence, proportions of carbapenemases, antibiotic susceptibility profiles, sample information, and patient outcomes. Complete plasmid sequencing data were utilized to investigate potential antimicrobial resistance or virulence advantages that strains may gain from acquiring redundant carbapenemases. RCP bacteria are widely distributed globally, and their prevalence is increasing over time. Several countries, including China, India, Iran, Turkey, and South Korea, have reported more than 100 RCP strains. The most commonly reported RCP species are Klebsiella pneumoniae and Acinetobacter baumannii, which exhibit varying proportions of carbapenemase combinations. Certain species-carbapenemase combinations, such as K. pneumoniae carrying New Delhi metallo-ß-lactamase (NDM) + oxacillinase (OXA) (56.76%) and K. pneumoniae carbapenemase (KPC) + Verona integron-encoded metallo-ß-lactamase (VIM) (50.00%) carbapenemases, are associated with high mortality rates. In patients with RCP strains isolated from the bloodstream and respiratory system, the mortality rates are 58.70% and 69.23%, respectively. Analysis of plasmids from RCP strains suggests that they may acquire additional antibiotic resistance phenotypes and virulence factors. Carbapenem-resistant bacteria carrying redundant carbapenemases pose a significant global health threat. This study provides valuable insights into the epidemiology and genetic mechanisms of these bacteria, supporting the development of effective control and prevention strategies to mitigate their transmission.IMPORTANCEThis study examined the global distribution patterns of 1,780 bacteria with double or multiple carbapenemases from 277 articles and assessed their clinical impact. The presence of multiple carbapenemases increases the chances of co-resistance to other classes of antibiotics and more virulence factors, further complicating the clinical management of infections.

Pan-cancer analysis of the intervertebral-disc-degeneration-related innate immunity gene NAIP.

BACKGROUND: Intervertebral disc degeneration (IDD) is a progressive chronic condition that commonly causes low back pain. Cancer is among the primary reasons for deaths worldwide. Our purpose was to identify the characteristic genes of IDD and explore the potential association between IDD and cancer. METHODS: Immune cell infiltration and differentially expressed analysis were conducted utilizing data from the GSE124272 database. Enrichment analysis of differentially expressed genes (DEGs) was performed to explore the possible mechanisms underlying IDD development. Moreover, weighted gene correlation network analysis (WGCNA) was applied to select IDD-related hub genes. The immune-related key genes were determined by intersecting DEGs, IDD-related hub genes, and immune genes. Subsequently, machine learning models based on these genes were built to identify and verify the characteristic genes. RNA sequencing and clinical data of 33 carcinoma categories were obtained from the Cancer Genome Atlas (TCGA). The association between NAIP expression and prognosis was calculated using the Kaplan-Meier analysis. To gain a deeper understanding of the impact of NAIP in tumor immunotherapy, the association between NAIP and immune infiltration and two immunotherapeutic biomarkers were explored. Ultimately, the association between NAIP and immunotherapeutic response was investigated utilizing two independent cohorts. RESULTS: NAIP was identified as an immune-related characteristic gene between IDD and normal intervertebral disc tissue. In certain carcinoma categories, NAIP expression levels were elevated (4/33) and significantly correlated to the respective tumor stage (4/21). Survival analysis revealed that the expression levels of NAIP have prognostic significance in different cancer types. Generally, NAIP presented a strong association with immune cell infiltration and modulators. NAIP may influence immunotherapy effects through tumor mutational burden and microsatellite instability. No remarkable association between NAIP and immunotherapy response was found in either cohort. CONCLUSION: Our study is the first to identify NAIP as an immune-related characteristic gene. Pan-cancer analysis revealed that NAIP could serve as a novel clinical prognostic marker and therapeutic target for a variety of carcinoma categories, reducing the risk of IDD in tumor patients.

An unusual presentation of ossified spinal meningioma: case report and literature review.

Background: Spinal meningioma is a common intraspinal tumor, which mainly occurs in the thoracic spine. Ossified meningioma (OSM) is an extremely rare histological variant. Our article reports a rare patient with dorsal complete OSM and reviews this subject. Case presentation: A 68-year-old woman presented with a one-year history of progressive weakness in both lower limbs with gait disturbance. Physical examination revealed hypoesthesia with a sensory level below T10. Babinski and pathological signs on both sides were weakly positive. Magnetic resonance imaging (MRI) showed a mass at the T10 to T11 level causing severe compression of the spinal cord. Computed tomography (CT) showed complete ossification of the mass. 18F-Fluoro-deoxy-glucose positron emission tomography CT (18F-FDG PET/CT) scan combined with MRI revealed that the mass was an intradural extramedullary high-density ossified nodule. The patient underwent a gross total resection of the mass and pathologic examination indicated that the mass was a meningioma with diffused psammomatous bodies. Conclusion: We identified a rare case of dorsal complete OSM occurring in a 68-year-old woman. After complete surgical resection, although there were complications such as cerebral fluid leakage and fever, the patient finally recovered with a satisfactory result.

Molecular Epidemiology, Microbial Virulence, and Resistance of Carbapenem-Resistant Enterobacterales Isolates in a Teaching Hospital in Guangzhou, China.

Infection caused by carbapenem-resistant Enterobacterales (CRE) is a global public health problem. We performed whole-genome sequencing to investigate the molecular epidemiological characteristics of local CRE infections and understand the prevalence of hypervirulent carbapenem-resistant Klebsiella pneumoniae (CRKP). Analysis of multiLocus sequence typing (MLST), antibiotic resistance genes, plasmid replicons, virulence genes, and the genetic environment was also performed. Klebsiella pneumoniae (89, 60.95%) was the most common CRE species, primarily prevalent in the intensive care unit (36, 40.45%). Most CRE strains showed a high resistance rate to multiple antibiotics, especially cephalosporins and carbapenems. However, most of these isolates were susceptible to tigecycline (81.7%). Notably, the predominant sequence type (ST) of CRKP isolates was ST11 (80.90%, 72/89), with 93.05% as Klebsiella pneumoniae carbapenemase (KPC)-ST11. In Escherichia coli isolates, ST410 (21.43%, 6/28) was the predominant type, with approximately half carrying blaNDM-5, and importantly, the ST167 carbapenem-resistant Escherichia coli (CRECO) harbors both New Delhi metallo-ß-lactamase (NDM)-5 and KPC-2. In Enterobacter cloacae isolates, three cases of ST88 were carrying the blaNDM-1 gene, and the ST594 carbapenem-resistant Enterobacter cloacae (CRECC) carrying NDM-1 and KPC-2 has also been identified. In addition, we found three novel STs, ST5386-ST5388. The IncFII (pHN7A8) (98.41%, 62/63) was the most common plasmid replicon type in KPC-2-producing CRKP strains, and the predominant plasmid ST of IncF was [f33:A-:B-] (n = 73). Two CRKP isolates were found to carry 4 virulence genes (iutA, iroB, rmpA, and rmpA2). As concluded, among CRKP strains, ST11 was the predominant ST with blaKPC-2, and a large proportion of CRKP strains co-harbor blaKPC-2, blaSHV, blaCTX-M, blaTEB-1B, and fosA. The predominant carbapenemase genes carried by CRECO and CRECC were blaNDM-1 and blaCTX-M, respectively.

Prevention, treatment and potential mechanism of herbal medicine for Corona viruses: A review.

The pandemic of coronavirus disease 2019 (COVID-19) caused by the SARS-coronavirus 2(SARS-CoV-2) virus has become the greatest global public health crisis in recent years,and the COVID-19 epidemic is still continuing. However, due to the lack of effectivetherapeutic drugs, the treatment of corona viruses is facing huge challenges. In thiscontext, countries with a tradition of using herbal medicine such as China have beenwidely using herbal medicine for prevention and nonspecific treatment of corona virusesand achieved good responses. In this review, we will introduce the application of herbalmedicine in the treatment of corona virus patients in China and other countries, andreview the progress of related molecular mechanisms and antiviral activity ingredients ofherbal medicine, in order to provide a reference for herbal medicine in the treatment ofcorona viruses. We found that herbal medicines are used in the prevention and fightagainst COVID-19 in countries on all continents. In China, herbal medicine has beenreported to relieve some of the clinical symptoms of mild patients and shorten the length of hospital stay. However, as most herbal medicines for the clinical treatment of COVID-19still lack rigorous clinical trials, the clinical and economic value of herbal medicines in theprevention and treatment of COVID-19 has not been fully evaluated. Future work basedon large-scale randomized, double-blind clinical trials to evaluate herbal medicines andtheir active ingredients in the treatment of new COVID-19 will be very meaningful.

Pan-Genome Analysis of Laribacter hongkongensis: Virulence Gene Profiles, Carbohydrate-Active Enzyme Prediction, and Antimicrobial Resistance Characterization.

Laribacter hongkongensis is a new emerging foodborne pathogen that causes community-acquired gastroenteritis and traveler's diarrhea. However, the genetic features of L. hongkongensis have not yet been properly understood. A total of 45 aquatic animal-associated L. hongkongensis strains isolated from intestinal specimens of frogs and grass carps were subjected to whole-genome sequencing (WGS), along with the genome data of 4 reported human clinical strains, the analysis of virulence genes, carbohydrate-active enzymes, and antimicrobial resistance (AMR) determinants were carried out for comprehensively understanding of this new foodborne pathogen. Human clinical strains were genetically more related to some strains from frogs inferred from phylogenetic trees. The distribution of virulence genes and carbohydrate-active enzymes exhibited different patterns among strains of different sources, reflecting their adaption to different host environments and indicating different potentials to infect humans. Thirty-two AMR genes were detected, susceptibility to 18 clinical used antibiotics including aminoglycoside, chloramphenicol, trimethoprim, and sulfa was checked to evaluate the availability of clinical medicines. Resistance to Rifampicin, Cefazolin, ceftazidime, Ampicillin, and ceftriaxone is prevalent in most strains, resistance to tetracycline, trimethoprim-sulfamethoxazole, ciprofloxacin, and levofloxacin are aggregated in nearly half of frog-derived strains, suggesting that drug resistance of frog-derived strains is more serious, and clinical treatment for L. hongkongensis infection should be more cautious.

Proteomics profiling of ertapenem challenged major porin deficient carbapenem-resistant Klebsiella pneumoniae.

Carbapenem-resistant Klebsiella pneumoniae (CRKP) is an urgent threat to human health. Major outer membrane proteins (OMPs) porin mutation is one important resistance mechanism of CRKP, and may also affect the inhibition activity of ß-lactam and ß-lactamase inhibitor combinations. The ertapenem-resistant K. pneumoniae strain 2018B120 with major porin mutations was isolated from a clinical patient. Genomic and time-series proteomic analyses were conducted to retrieve the ertapenem-challenged response of 2018B120. The abundance changing of proteins from PTS systems,  ABC transporters, the autoinducer 2 (AI-2) quorum sensing system, and antioxidant systems can be observed. Overexpression of alternative porins was also noticed to balance major porins' defection. These findings added a detailed regulation network in bacterial resistance mechanisms and gave new insights into bypass adaptation mechanisms the porin deficient bacteria adopted under carbapenem antibiotics pressure. SIGNIFICANCE: Outer membrane porins deficiency is an important mechanism of carbapenem resistance in K. pneumoniae. Comprehensive genomic and proteomic profiling of an ertapenem-resistant K. pneumoniae strain 2018B120 gives a detailed systematic regulation network in bacterial resistance mechanisms. Overexpression of alternative porins to balance major porins' defection was noticed, giving new insights into bypass adaptation mechanisms of porin deficient bacteria.