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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.

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.

Background The dissemination of multi-drug-resistant bacteria, particularly Methicillin-resistant Staphylococcus aureus (MRSA), necessitates exploring new alternatives for their control. Bacteriophages are promising antibiotic alternatives with unique features. Here, we have performed a comprehensive characterization of a newly isolated bacteriophage (PSK) and compared its therapeutic potential with vancomycin in vivo. Methods Sewage samples were processed and enriched with the MRSA S. aureus SK1 strain in a search for isolation of a lytic bacteriophage. The isolated bacteriophage was assessed in vitro in terms of thermal and pH stability and kinetic parameters using absorption and one step growth curve assays. Moreover, its potential antibacterial activity was evaluated against S. aureus SK1 lone and in combination of standard of care antibiotics used for treatment of wound infections. We further analyzed its genome to exclude the presence of any potential toxin or antibiotic resistance genes. Finally, its antibacterial potential and capability to alleviate wound infection were assessed using a murine wound-infection model. Results The lytic bacteriophage (PSK) was isolated as a new species of the genus Rosenblumvirus with a genome size of 17,571 bp that is free from potential resistance or virulence genes. PSK displays infectivity against 4/10 S. aureus strains including two vancomycin-resistant strains. Moreover, it demonstrates favorable infection kinetics of fast adsorption with latent period and burst size of 20 min and 123 PFU/infected cell, respectively. Stability analysis revealed thermal stability up to 60 °C with wide pH range stability (4–11). In vitro, PSK kills S. aureus SK1 with multiplicity of infection (MOI) as low as 10 − 4 with an overall mutation frequency of 2.47 × 10 − 6 CFU/mL that is further improved when combined with 0.25× MIC of oxacillin, fusidic acid or vancomycin. In vivo, a single dose of PSK in murine wound infection model exhibited a comparable performance to four doses of vancomycin, when treatment started 2 h post-infection. However, when applied 2 days post-infection, PSK demonstrates superior antibacterial activity (up to 4.58 log unit count reduction) and enhances wound closure and tissue healing. Conclusion These findings represent PSK as a potential vancomycin alternative effective in treating S. aureus - induced wound infections.

As a result of the growing prevalence of the plasmid-mediated mobile colistin resistance gene among Gram-negative bacteria, the surveillance of has been globally applied. In our study, we aimed to shed light on the possibility of transmission of -resistant isolates through market retail fruits. Herein, 133 different fruit surface samples were collected and screened for the different MCR variants ( to ) using PCR and confirmed with sequencing. We identify for the first time -carrying and from market retail fruits in Guangzhou, China. Minimum inhibitory concentrations were detected by the broth microdilution method. Liquid mating was performed to check the transferability of the gene. Pulsed field gel electrophoresis analysis of S1 nuclease-digested DNA and Southern blotting were performed to check the location of the gene. Then, whole-genome sequencing and in silico multilocus sequence typing analysis were performed. We showed that GB110 can mediate the spreading of antibiotic resistance genes through the food chain, while GB015 was considered to be the progenitor of the most successful multidrug-resistant clone. Since fruits are usually consumed fresh, this may serve as a direct source of -producing bacteria in humans that requires prompt surveillance and intervention to limit the spread of resistance.

The main objective of this study was to decipher the prevalence, antimicrobial resistance, major virulence genes and the molecular characteristics of methicillin-resistant (MRSA) isolated from different clinical sources in southern China. The present study was performed on 187 non-duplicate clinical isolates collected from three tertiary hospitals in Guangdong Province, China, 2010-2016. Antimicrobial susceptibility testing was performed by the disk diffusion method and by measuring the minimum inhibitory concentration. Screening for resistance and virulence genes was performed. Clonal relatedness was determined using various molecular typing methods such as multilocus sequence typing, and staphylococcal chromosomal cassette mec (SCCmec) typing. Whole genome sequencing was performed for three selected isolates. Out of 187 isolates, 103 (55%) were identified as MRSA. The highest prevalence rate was found among the skin and soft tissue infection (SSTI) samples (58/103), followed by sputum samples (25/103), blood stream infection samples (15/103) and others (5/103). Antimicrobial susceptibility results revealed high resistance rates for erythromycin (64.1%), clindamycin (48.5%), gentamicin (36.9%) and ciprofloxacin (33.98%). All isolates were susceptible to vancomycin. Resistance genes and mutation detected were as follows: ' \") (24.3%), (10.7%), (21.4%), (0%), (1.94%), (35.92%), (0.97%), (20.4%), (10.68%), (21.4%), (18.44%), (21.4%) and (18.44%). Profiling of virulence genes revealed the following: (11.7%), (21.4%), (0.97%), (0.97%), (86.41%), (17.48%), (10.68%), (53.4%), (3.9%) and (27.2%). Clonal relatedness showed that ST239-SCCmecA III-t37 clone was the most prevalent clone. Our study elucidated the prevalence, antibiotic resistance, pathogenicity and molecular characteristics of MRSA isolated from various clinical sources in Guangdong, China. We found that the infectious rate of MRSA was higher among SSTI than other sources. The most predominant genotype was ST239-SCCmecA III-t37 clone, indicating that ST239-t30 clone which was previously predominant had been replaced by a new clone.

The discovery of the plasmid-mediated colistin resistance genes, , revealed a mechanism of transmission of colistin resistance, which is a major, global public health concern especially among individuals infected with carbapenem-resistant Gram-negative bacteria. To monitor the spread and epidemiology of genes, a convenient and reliable method to detect genes in clinical isolates is needed, especially in the primary care institutions. This study aimed to establish a restriction endonuclease-based multiplex loop-mediated isothermal amplification (multi-LAMP) assay to detect genes ( to ) harbored by colistin-resistant bacteria. A triple-LAMP assay for , and and a double-LAMP assay for and were established. The sensitivity and specificity of the LAMP reactions were determined via electrophoresis and visual detection. The sensitivity of the LAMP assay was 10-fold greater than that of PCR, with high specificity among the screened primers. Specific genes were distinguished in accordance with band numbers and the fragment length of the digested LAMP amplification products. Furthermore, the LAMP assay was confirmed as a rapid and reliable diagnostic technique upon application for clinical samples, and the results were consistent with those of conventional PCR assay. The multi-LAMP assay is a potentially promising method to detect genes and will, if implemented, help prevent infections by drug-resistant bacteria in primary-care hospitals due to rapid and reliable surveillance. To our knowledge, this is the first study to report the application of LAMP to detect to genes and the first time that multi-LAMP has been applied to detect genes.

The emergence and transmission of the mobile colistin resistance gene ( mcr - 1 ) threatened the extensive use of polymyxin antimicrobials. Accumulated evidence showed that the banning of colistin additive in livestock feed efficiently reduce mcr - 1 prevalence, not only in animals but also in humans and environments. However, our previous study has revealed that a small proportion of Escherichia coli could continually carry chromosomally-encoded mcr - 1 . The chromosomally-encoded events, indicated the existence of stabilized heritage of mcr - 1 and revealed a potential threat in the antimicrobial stewardship interventions, are yet to be investigated. In this study, we systematically investigated the genetic basis of chromosomally-encoded mcr - 1 in prevalence and potential mechanisms of lineage, plasmid, insertion sequence, and phage. Our results demonstrated that the emergence of chromosomally-encoded mcr - 1 could originate from multiple mechanisms, but mainly derived through the recombination of IS Apl1 /Tn 6330 . We reported a specific transmission mechanism, which is a phage-like region without lysogenic components, could associate with the emergence and stabilization of chromosomally-encoded mcr - 1 . These results highlighted the potential origin and risks of chromosomally-encoded mcr - 1 , which could be a heritable repository and thrive again when confronted with new selective pressures. To the best of our knowledge, this is the first study to systematically reveal the genomic basis of chromosomally-encoded mcr - 1 , and report a specific transmission pattern involved in phage-like region. Overall, we demonstrate the origin mechanisms and risks of chromosomally-encoded mcr - 1 . It highlights the need of public attention on chromosome-encoded mcr - 1 to prevent from its reemergence.

Chlorhexidine Hydrochloride [Chx.HCl] has a broad-spectrum antibacterial effect, sustained action and low toxicity so it has been recommended as a potential root canal irrigant. The aim of this study was to improve the penetration ability, cleansing and antibacterial effect of Chx.HCl using a newly formulated Chx.HCl nanoemulsion and use it as root canal irrigant. Chx.HCl nanoemulsions were prepared using two different oils; Oleic acid and Labrafil M1944CS, two surfactants; Tween 20 and Tween 80 and co-surfactant; Propylene Glycol. Pseudoternary phase diagrams were constructed to designate the optimum systems. The prepared nanoemulsion formulae were evaluated for their drug content, emulsification time, dispersibility, droplet size, in-vitro drug release, thermodynamic stability, In-vitro antibacterial activity and ex-vivo study for the selected formula. Comparisons were made of Chx.HCl nanoemulsion with two different concentrations 0.75% and 1.6% vs Chx.HCl normal particle size as root canal irrigant for their penetration ability, cleansing effect and antibacterial effect. The selected formula was F6 with composition of 2% Labrafil, 12% Tween 80 and 6% Propylene glycol. It has small particle size (12.18 nm), short emulsification time (1.67 seconds), and fast dissolution rate after 2 minutes. It was found to be a thermodynamically/physically stable system. The higher concentration of Chx.HClnanoemulsion1.6% shows the best penetration ability compared to Chx.HCl normal particle size due to the smaller particle size. Chx.HCl nanoemulsion 1.6% has the lowest mean value of the remaining debris surface area (2001.47 µm ) when compared to normal particle size material (2609.56 µm ). Chx.HCl nanoemulsion preparation has better cleansing ability and antibacterial effect with high efficacy on , where high reduction rate or complete eradication of bacterial cells has been achieved.

Background: Bloodstream infection (BSI) caused by carbapenem-resistant Enterobacteriaceae are potentially life-threatening related to poorer outcomes. Colistin is considered one of the last-resort treatments against human infections caused by multidrug-resistant (MDR) Gram-negative bacteria. Therefore, emergence of strains from the blood that co-harboring mcr and carbapenem resistance genes were considered as a serious problem. Purpose: In this study, two mcr-9-harboring MDR Enterobacter cloacae isolates BSI034 and BSI072 recovered from BSI patients were identified, one of which co-harbored mcr-9 and blaNDM-1. The genetic characteristics of the MDR plasmid needed to be clarified. Methods: S1-PFGE and Southern blotting were conducted to determine the location of mcr-9. Whole-genome sequencing was performed to obtain the complete genome and plasmid sequences. The resistome and virulence genes of the strains, accompanied by the genetic characteristics of mcr-9- and blaNDM-1-harboring plasmids, were analyzed. Results: Whole-genome sequencing showed that BSI034 harbored mcr-9-carrying IncHI2-type pBSI034-MCR9 and blaNDM-1-carrying IncX3-type pBSI034-NDM1. The 278,517 bp pBSI034-MCR9 carried mcr-9 along with the other 19 resistance genes. mcr-9 was flanked by IS903B (1057 bp) and IS26 (820 bp) in the same orientation. In addition to resistance genes, strain BSI034 also carried a chromosome-located Yersinia high-pathogenicity island, which harbored genes of yersiniabactin biosynthesis operon ybtSXQPAUTE, irp1/2, and fyuA. Conclusion: We described the complete genome and mcr-9/blaNDM-1-co-harboring plasmid of E. cloacae from a BSI patient. Notable differences were observed within mosaic modules between pBSI034-MCR9 and other mcr-9-harboring plasmids due to extensive recombination via horizontal gene transfer.

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.