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Increasing antibiotic resistance in multidrug-resistant (MDR) Gram-negative bacteria (MDR-GNB) presents significant health problems worldwide, since the vital available and effective antibiotics, including; broad-spectrum penicillins, fluoroquinolones, aminoglycosides, and β-lactams, such as; carbapenems, monobactam, and cephalosporins; often fail to fight MDR Gram-negative pathogens as well as the absence of new antibiotics that can defeat these \"superbugs\". All of these has prompted the reconsideration of old drugs such as polymyxins that were reckoned too toxic for clinical use. Only two polymyxins, polymyxin E (colistin) and polymyxin B, are currently commercially available. Colistin has re-emerged as a last-hope treatment in the mid-1990s against MDR Gram-negative pathogens due to the development of extensively drug-resistant GNB. Unfortunately, rapid global resistance towards colistin has emerged following its resurgence. Different mechanisms of colistin resistance have been characterized, including intrinsic, mutational, and transferable mechanisms. In this review, we intend to discuss the progress over the last two decades in understanding the alternative colistin mechanisms of action and different strategies used by bacteria to develop resistance against colistin, besides providing an update about what is previously recognized and what is novel concerning colistin resistance.

The mcr-1 gene confers transferable colistin resistance. mcr-1-positive Enterobacteriaceae (MCRPE) have attracted substantial medical, media, and political attention; however, so far studies have not addressed their clinical impact. Herein, we report the prevalence of MCRPE in human infections and carriage, clinical associations of mcr-1-positive Escherichia coli (MCRPEC) infection, and risk factors for MCRPEC carriage. We undertook this study at two hospitals in Zhejiang and Guangdong, China. We did a retrospective cross-sectional assessment of prevalence of MCRPE infection from isolates of Gram-negative bacteria collected at the hospitals from 2007 to 2015 (prevalence study). We did a retrospective case-control study of risk factors for infection and mortality after infection, using all MCRPEC from infection isolates and a random sample of mcr-1-negative E coli infections from the retrospective collection between 2012 and 2015 (infection study). We also did a prospective case-control study to assess risk factors for carriage of MCRPEC in rectal swabs from inpatients with MCRPEC and mcr-1 negative at the hospitals and collected between May and December, 2015, compared with mcr-1-negative isolates from rectal swabs of inpatients (colonisation study). Strains were analysed for antibiotic resistance, plasmid typing, and transfer analysis, and strain relatedness. We identified 21 621 non-duplicate isolates of Enterobacteriaceae, Acinetobacter spp, and Pseudomonas aeruginosa from 18 698 inpatients and 2923 healthy volunteers. Of 17 498 isolates associated with infection, mcr-1 was detected in 76 (1%) of 5332 E coli isolates, 13 (<1%) of 348 Klebsiella pneumoniae, one (<1%) of 890 Enterobacter cloacae, and one (1%) of 162 Enterobacter aerogenes. For the infection study, we included 76 mcr-1-positive clinical E coli isolates and 508 mcr-1-negative isolates. Overall, MCRPEC infection was associated with male sex (209 [41%] vs 47 [63%], adjusted p=0·011), immunosuppression (30 [6%] vs 11 [15%], adjusted p=0·011), and antibiotic use, particularly carbapenems (45 [9%] vs 18 [24%], adjusted p=0·002) and fluoroquinolones (95 [19%] vs 23 [30%], adjusted p=0·017), before hospital admission. For the colonisation study, we screened 2923 rectal swabs from healthy volunteers, of which 19 were MCRPEC, and 1200 rectal swabs from patients, of which 35 were MCRPEC. Antibiotic use before hospital admission (p<0·0001) was associated with MCRPEC carriage in 35 patients compared with 378 patients with mcr-1-negative E coli colonisation, whereas living next to a farm was associated with mcr-1-negative E coli colonisation (p=0·03, univariate test). mcr-1 could be transferred between bacteria at high frequencies (10−1 to 10−3), and plasmid types and MCRPEC multi-locus sequence types (MLSTs) were more variable in Guangdong than in Zhejiang and included the human pathogen ST131. MCRPEC also included 17 unreported ST clades. In 2017, colistin will be formally banned from animal feeds in China and switched to human therapy. Infection with MRCPEC is associated with sex, immunosuppression, and previous antibiotic exposure, while colonisation is also associated with antibiotic exposure. MLST and plasmid analysis shows that MCRPEC are diversely spread throughout China and pervasive in Chinese communities. National Key Basic Research Program of China, National Natural Science Foundation of China/Zhejiang, National Key Research and Development Program, and MRC, UK.

Three-wave resonant interactions are commonly observed in the dispersive and weakly nonlinear media in fluid mechanics, plasma physics, nonlinear optics, solid-state physics, Bose–Einstein condensates and acoustics. This paper investigates a three-wave resonant interaction system in the one-dimensional space-time form. For that system of the soliton-exchange case, a Lax pair is introduced. Then, we utilize the generalized Darboux transformation method to derive the semi-rational solutions depicting the bound-state dark–bright mixed solitons. The three wave packets can manifest themselves as the bound-state bright–dark–bright solitons on the zero–nonzero–zero background, and bound-state dark–bright–bright solitons on the nonzero–zero–zero background. The bound states between the bright/dark solitons exhibit periodic attractions and repulsions, while the bound states among the bright/dark solitons and multi-pole bright/dark solitons exhibit non-periodic attractions and repulsions. We explore how the phase shift of the single bright/dark soliton component affects the bound states among a single bright/dark soliton and the double-pole bright/dark solitons. All the results obtained for the one-dimensional space-time evolution can be reinterpreted in terms of the two-dimensional steady-state interaction. This work may provide explanations for the complex and variable natural mechanisms of three-wave resonant interactions in various physical contexts.

Glioblastoma multiforme (GBM) is the most common and malignant type of primary brain tumor in adults. Despite important advances in understanding the molecular pathogenesis and biology of this tumor in the past decade, the prognosis for GBM patients remains poor. GBM is characterized by aggressive biological behavior and high degrees of inter-tumor and intra-tumor heterogeneity. Increased understanding of the molecular and cellular heterogeneity of GBM may not only help more accurately define specific subgroups for precise diagnosis but also lay the groundwork for the successful implementation of targeted therapy. Herein, we systematically review the key achievements in the understanding of GBM molecular pathogenesis, mechanisms, and biomarkers in the past decade. We discuss the advances in the molecular pathology of GBM, including genetics, epigenetics, transcriptomics, and signaling pathways. We also review the molecular biomarkers that have potential clinical roles. Finally, new strategies, current challenges, and future directions for discovering new biomarkers and therapeutic targets for GBM will be discussed.

The emerging and global spread of a novel plasmid-mediated colistin resistance gene, mcr-1 , threatens human health. Expression of the MCR-1 protein affects bacterial fitness and this cost correlates with lipid A perturbation. However, the exact molecular mechanism remains unclear. Here, we identified the MCR-1 M6 variant carrying two-point mutations that conferred co-resistance to β-lactam antibiotics. Compared to wild-type (WT) MCR-1, this variant caused severe disturbance in lipid A, resulting in up-regulation of L, D-transpeptidases (LDTs) pathway, which explains co-resistance to β-lactams. Moreover, we show that a lipid A loading pocket is localized at the linker domain of MCR-1 where these 2 mutations are located. This pocket governs colistin resistance and bacterial membrane permeability, and the mutated pocket in M6 enhances the binding affinity towards lipid A. Based on this new information, we also designed synthetic peptides derived from M6 that exhibit broad-spectrum antimicrobial activity, exposing a potential vulnerability that could be exploited for future antimicrobial drug design.

Background Emergence and global expansion of the multidrug-resistant (MDR) clones of Acinetobacter baumannii which often cause difficult-to-treat infections, have been increasingly reported in nosocomial and community-acquired infections. However, as the most widely prevalent sequence type of MDR A. baumannii , the distribution and evolution of ST2 A. baumannii remain obscure. In this study, a multicenter epidemiological survey was conducted using A. baumannii isolates obtained from 27 provinces and municipalities across China between 1999 and 2022. Results It was observed that ST2 was the most common sequence type among the A. baumannii isolates in China. Subsequently, 143 representative ST2 isolates were selected for genomic and evolutionary analyses. Out of these, 23 isolates were collected in this study, while an additional 120 isolates were downloaded from the GenBank database. We demonstrated that ST2 A. baumannii strains had diverse phylogenetic structures with nine sequence clusters (SCs). Extensive recombination events related to capsular polysaccharides and phages were detected, enabling distinction between different SCs. A high number of antibiotic resistance genes (ARGs) (Median 30 [range 22 to 36]) were identified, with 23 strains in this study showing pandrug resistance. All 143 ST2 strains were found to carry genes associated with antibiotic efflux pumps, such as amv A, ade GH and ade IJK, abe S, and abe M, with a most recent common ancestor (MRCA) arose around 1976. Antimicrobial susceptibility testing (AST) showed that 23 isolates collected in this study were resistant to meropenem. Extensive presence of A. baumannii genomic resistance islands (AbGRIs), including AbGRI1, AbGRI2, and AbGRI3, was observed within ST2 A. baumannii , with multiple resistance genes co-located. Conclusions This study demonstrated the homologous recombination and antibiotic resistance contribute to evolution of ST2 A. baumannii , with a MRCA arose around 1976 in China. The results are highly relevant for enhancing the understanding of ST2 A. baumannii diversity and evolutionary pathways among practitioners, researchers and policymakers, informing infection reduction strategies.

Abstract The antibiotic resistance crisis continues to threaten human health. Better predictions of the evolution of antibiotic resistance genes could contribute to the design of more sustainable treatment strategies. However, comprehensive prediction of antibiotic resistance gene evolution via laboratory approaches remains challenging. By combining site-specific integration and high-throughput sequencing, we quantified relative growth under the respective selection of cefotaxime or ceftazidime selection in ∼23,000 Escherichia coli MG1655 strains that each carried a unique, single-copy variant of the extended-spectrum β-lactamase gene blaCTX-M-14 at the chromosomal att HK022 site. Significant synergistic pleiotropy was observed within four subgenic regions, suggesting key regions for the evolution of resistance to both antibiotics. Moreover, we propose PEARP and PEARR, two deep-learning models with strong clinical correlations, for the prospective and retrospective prediction of blaCTX-M-14 evolution, respectively. Single to quintuple mutations of blaCTX-M-14 predicted to confer resistance by PEARP were significantly enriched among the clinical isolates harboring blaCTX-M-14 variants, and the PEARR scores matched the minimal inhibitory concentrations obtained for the 31 intermediates in all hypothetical trajectories. Altogether, we conclude that the measurement of local fitness landscape enables prediction of the evolutionary trajectories of antibiotic resistance genes, which could be useful for a broad range of clinical applications, from resistance prediction to designing novel treatment strategies.

Bloodstream infections (BSIs) caused by carbapenem-resistant Klebsiella pneumoniae (CRKP) are potentially life-threatening and an urgent threat to public health. The present study aims to clarify the characteristics of carbapenemase-encoding and virulent plasmids, and their interactions with the host bacterium. A total of 425 Kp isolates were collected from the blood of BSI patients from nine Chinese hospitals, between 2005 and 2019. Integrated epidemiological and genomic data showed that ST11 and ST307 Kp isolates were associated with nosocomial outbreak and transmission. Comparative analysis of 147 Kp genomes and 39 completely assembled chromosomes revealed extensive interruption of acrR by ISKpn26 in all Kp carbapenemase-2 (KPC-2)-producing ST11 Kp isolates, leading to activation of the AcrAB-Tolc multidrug efflux pump and a subsequent reduction in susceptibility to the last-resort antibiotic tigecycline and six other antibiotics. We described 29 KPC-2 plasmids showing diverse structures, two virulence plasmids in two KPC-2-producing Kp, and two novel multidrug-resistant (MDR)-virulent plasmids. This study revealed a multifactorial impact of KPC-2 plasmid on Kp, which may be associated with nosocomial dissemination of MDR isolates.

The global dissemination of the mobilized colistin resistance gene, mcr-1, threatens human health. Recent studies by our group and others have shown that the withdrawal of colistin as a feed additive dramatically reduced the prevalence of mcr-1. Although it is accepted that the rapid reduction in mcr-1 prevalence may have resulted, to some extent, from the toxic effects of MCR-1, the detailed mechanism remains unclear. Here, we found that MCR-1 damaged the outer membrane (OM) permeability in Escherichia coli and Klebsiella pneumonia and that this event was associated with MCR-1-mediated cell shrinkage and death during the stationary phase. Notably, the capacity of MCR-1-expressing cells for recovery from the stationary phase under improved conditions was reduced in a time-dependent manner. We also showed that mutations in the potential lipid-A-binding pocket of MCR-1, but not in the catalytic domain, restored OM permeability and cell viability. During the stationary phase, PbgA, a sensor of periplasmic lipid-A and LpxC production that performed the first step in lipid-A synthesis, was reduced after MCR-1 expression, suggesting that MCR-1 disrupted lipid homeostasis. Consistent with this, the overexpression of LpxC completely reversed the MCR-1-induced OM permeability defect. We propose that MCR-1 causes lipid remodelling that results in an OM permeability defect, thus compromising the viability of Gram-negative bacteria. These findings extended our understanding of the effect of MCR-1 on bacterial physiology and provided a potential strategy for eliminating drug-resistant bacteria.

In response to the spread of colistin resistance gene mcr-1, China banned the use of colistin in livestock fodders. We used a time-series analysis of inpatient colonization data from 2011-2019 to accurately reveal the associated fluctuations of mcr-1 that occurred in inpatients in response to the ban.