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Intestinal commensal bacteria can inhibit dense colonization of the gut by vancomycin-resistant Enterococcus faecium (VRE), a leading cause of hospital-acquired infections 1 , 2 . A four-strained consortium of commensal bacteria that contains Blautia producta BP SCSK can reverse antibiotic-induced susceptibility to VRE infection 3 . Here we show that BP SCSK reduces growth of VRE by secreting a lantibiotic that is similar to the nisin-A produced by Lactococcus lactis . Although the growth of VRE is inhibited by BP SCSK and L. lactis in vitro, only BP SCSK colonizes the colon and reduces VRE density in vivo. In comparison to nisin-A, the BP SCSK lantibiotic has reduced activity against intestinal commensal bacteria. In patients at high risk of VRE infection, high abundance of the lantibiotic gene is associated with reduced density of E. faecium . In germ-free mice transplanted with patient-derived faeces, resistance to VRE colonization correlates with abundance of the lantibiotic gene. Lantibiotic-producing commensal strains of the gastrointestinal tract reduce colonization by VRE and represent potential probiotic agents to re-establish resistance to VRE. The gut commensal Blautia producta secretes a lantibiotic that reduces colonization of the gut by the major pathogen vancomycin-resistant Enterococcus faecium , and transplantation of microbiota with high abundance of the lantibiotic gene enhances resistance to colonization in mice.

Key Points Enterococci are some of the most versatile organisms found to infect hospitalized patients. The epidemiology of enterococcal infections has evolved since the emergence of these pathogens and has seen the rise of Enterococcus faecium as a nosocomial pathogen with serious clinical implications. The effect of antibiotics on the microbiota of the gastrointestinal tract and subsequent alterations in the regulation of the gut immune system can favour colonization by multidrug-resistant enterococci. Enterococcal genomes are extremely malleable, with the ability to exchange large fragments of chromosomal DNA. In addition, the lack of CRISPR (clustered regularly interspaced short palindromic repeats) elements has a potential role in the adaptation of hospital-associated enterococci. Specific pathogenicity factors contribute to the ability of enterococci to produce disease and/or survive in the gastrointestinal tract of mammals. The major factors include secreted and cell surface-associated determinants. Antibiotic resistance is widespread for the anti-enterococcal antibiotics that are most commonly used in clinical practice, and the mechanisms of resistance for many of these antibiotics are known. These antibiotics include ampicillin, linezolid, daptomycin and quinupristin–dalfopristin, and there is also high-level resistance to aminoglycosides. Such resistances have important therapeutic implications. Arias and Murray discuss the factors that may have contributed to the rise of enterococci as nosocomial pathogens, with an emphasis on the epidemiology and pathogenesis of these species and their mechanisms of resistance to the most relevant anti-enterococcal agents used in clinical practice. The genus Enterococcus includes some of the most important nosocomial multidrug-resistant organisms, and these pathogens usually affect patients who are debilitated by other, concurrent illnesses and undergoing prolonged hospitalization. This Review discusses the factors involved in the changing epidemiology of enterococcal infections, with an emphasis on Enterococcus faecium as an emergent and challenging nosocomial problem. The effects of antibiotics on the gut microbiota and on colonization with vancomycin-resistant enterococci are highlighted, including how enterococci benefit from the antibiotic-mediated eradication of Gram-negative members of the gut microbiota. Analyses of enterococcal genomes indicate that there are certain genetic lineages, including an E. faecium clade of ancient origin, with the ability to succeed in the hospital environment, and the possible virulence determinants that are found in these genetic lineages are discussed. Finally, we review the most important mechanisms of resistance to the antibiotics that are used to treat vancomycin-resistant enterococci.

Vancomycin is a glycopeptide antibiotic used for the treatment of Gram-positive bacterial infections. Traditionally, it has been used as a drug of last resort; however, clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) strains with decreased susceptibility to vancomycin (vancomycin intermediate-resistant S. aureus [VISA]) and more recently with high-level vancomycin resistance (vancomycin-resistant S. aureus [VRSA]) have been described in the clinical literature. The rare VRSA strains carry transposon Tn1546, acquired from vancomycin-resistant Enterococcus faecalis, which is known to alter cell wall structure and metabolism, but the resistance mechanisms in VISA isolates are less well defined. Herein, we review selected mechanistic aspects of resistance in VISA and summarize biochemical studies on cell wall synthesis in a VRSA strain. Finally, we recapitulate a model that integrates common mechanistic features of VRSA and VISA strains and is consistent with the mode of action of vancomycin.

We investigated genomic evolution of vancomycin-resistant Enterococcus faecium (VREF) during an outbreak in Shenzhen, China. Whole-genome sequencing revealed 2 sequence type 80 VREF subpopulations diverging through insertion sequence-mediated recombination. One subpopulation acquired more antimicrobial resistance and carbohydrate metabolism genes. Persistent VREF transmission underscores the need for genomic surveillance to curb spread.

The roots of antibiotic resistance Antibiotic resistance is thought to have evolved long before naturally occurring antibiotics and their derivatives were used to treat human disease, but direct evidence for genes that encode resistance has been lacking. Now, an ancient vancomycin-resistance gene has been recovered from 30,000-year-old samples of Siberian permafrost, and the three-dimensional structure of its product has been compared with that of its modern counterpart. There are minor structural differences between the ancient and modern versions, but the differences are not reflected in enzyme function. The discovery of antibiotics more than 70 years ago initiated a period of drug innovation and implementation in human and animal health and agriculture. These discoveries were tempered in all cases by the emergence of resistant microbes 1 , 2 . This history has been interpreted to mean that antibiotic resistance in pathogenic bacteria is a modern phenomenon; this view is reinforced by the fact that collections of microbes that predate the antibiotic era are highly susceptible to antibiotics 3 . Here we report targeted metagenomic analyses of rigorously authenticated ancient DNA from 30,000-year-old Beringian permafrost sediments and the identification of a highly diverse collection of genes encoding resistance to β-lactam, tetracycline and glycopeptide antibiotics. Structure and function studies on the complete vancomycin resistance element VanA confirmed its similarity to modern variants. These results show conclusively that antibiotic resistance is a natural phenomenon that predates the modern selective pressure of clinical antibiotic use.

Abstract BACKGROUND: Surgical site infection (SSI) following spine surgery is a morbid and expensive complication. The use of intrawound vancomycin is emerging as a solution to reduce SSI. The development of vancomycin-resistant pathogens is an understandable concern. OBJECTIVE: To determine the occurrence of vancomycin-resistant SSI in patients with and without use of intrawound vancomycin. METHODS: Patients undergoing elective spine surgery were dichotomized based on whether intrawound vancomycin was applied. Outcome was occurrence of SSI requiring return to the operating room within postoperative 90 days. The intrawound culture and vancomycin minimal inhibitory concentrations (MIC) were reviewed. Analyses were conducted to compare the pathogen profile and MIC for vancomycin in patients who received vancomycin and those who did not. RESULTS: Of the total 2802 patients, 43% (n = 1215) had intrawound vancomycin application during the index surgery. The use of vancomycin was associated with significantly lower deep SSI rates (1.6% [n = 20] vs 2.5% [n = 40], P = .02). The occurrence of Staphylococcus aureus SSI was significantly lower in the patients who had application of intrawound vancomycin (32% vs 65%, P = .003). None of the patients who had application of intrawound vancomycin powder, and subsequently developed an S aureus SSI, demonstrated pathogens with resistance to vancomycin. All patients had MIC < 2 μg/mL, the vancomycin susceptibility threshold. The occurrence of gram-negative SSI (28% vs 7%) and culture negative fluid collection (16% vs 5%) was higher in the vancomycin cohort. CONCLUSIONS: The use of intrawound vancomycin during the index spine surgery was protective against SSI following spine surgery. The application of intrawound vancomycin during index surgery does not appear to create vancomycin-resistant organisms in the event of an SSI.

Methicillin-resistant Staphylococcus aureus (MRSA) infection is an important clinical concern in patients, and is often associated with significant disease burden and metastatic infections. There is an increasing evidence of heterogeneous vancomycin-intermediate S. aureus (hVISA) associated treatment failure. In this study, we aim to understand the molecular mechanism of teicoplanin resistant MRSA (TR-MRSA) and hVISA. A total of 482 MRSA isolates were investigated for these phenotypes. Of the tested isolates, 1% were identified as TR-MRSA, and 12% identified as hVISA. A highly diverse amino acid substitution was observed in tcaRAB, vraSR, and graSR genes in TR-MRSA and hVISA strains. Interestingly, 65% of hVISA strains had a D148Q mutation in the graR gene. However, none of the markers were reliable in differentiating hVISA from TR-MRSA. Significant pbp2 upregulation was noted in three TR-MRSA strains, which had teicoplanin MICs of 16 or 32 μg/ml, whilst significant pbp4 downregulation was not noted in these strains. In our study, multiple mutations were identified in the candidate genes, suggesting a complex evolutionary pathway involved in the development of TR-MRSA and hVISA strains.

The first vancomycin-resistant clinical isolates of Enterococcus species were reported in Europe in 1988. Similar strains were later detected in hospitals on the East Coast of the United States. Since then, vancomycin-resistant enterococci have spread with unexpected rapidity and are now encountered in hospitals in most countries. This article reviews the mode of action and the mechanism of bacterial resistance to glycopeptides, as exemplified by the VanA type, which is mediated by transposon Tn1546 and is widely spread in enterococci. The diversity, regulation, evolution, and recent dissemination of methicillin-resistant Staphylococcus aureus are then discussed.

Background Multidrug resistant (MDR) and biofilm producing Staphylococcus aureus strains are usually associated with serious infections. This study aimed to evaluate the antibacterial and antibiofilm-formation effects of zinc oxide nanoparticles (ZnO-NPs) against staphylococcus aureus ( S. aureus) isolates. Methods A total of 116 S. aureus isolates were recovered from 250 burn wound samples. The antimicrobial/antibiofilm effects of ZnO-NPs against methicillin, vancomycin and linezolid resistant S. aureus (MRSA, VRSA and LRSA) isolates were examined using phenotypic and genotypic methods. The minimum inhibitory concentration (MIC) of ZnO-NPs was determined by microdilution method. The effects of sub-MIC concentrations of ZnO-NPs on biofilm formation and drug resistance in S. aureus were determined by the microtiter plate method. The change in the expression levels of the biofilm encoding genes and resistance genes in S. aureus isolates after treatment with ZnO-NPs was assessed by real time reverse transcriptase PCR (rt-PCR). Results MICs of ZnO-NPs in S. aureus isolates were (128–2048 µg/ml). The sub-MIC of ZnO-NPs significantly reduced biofilm formation rate (the highest inhibition rate was 76.47% at 1024  µg/ml) and the expression levels of biofilm genes ( ica A, ica D and fnb A) with P < 0.001. Moreover, Sub-MIC of ZnO-NPs significantly reduced the rates of MRSA from 81.9 (95 isolates) to 13.30% (15 isolates), VRSA from 33.60 (39 isolates) to 0% and LARSA from 29.30 (34) to 0% as well as the expression levels of resistance genes ( mec A, van A and cfr ) with P value < 0.001. Conclusion ZnO-NPs can be used as antibiofilm and potent antimicrobial against MRSA, VRSA and LRSA isolates.

ABSTRACT The increasing spread of antibiotic resistant bacteria is a major human health concern. The challenging development of new effective antibiotics has led to focus on seeking synergistic antibiotic combinations. Vancomycin (VAN) is a glycopeptide antibiotic used to treat Staphylococcus aureus and enterococci infections. It is targeting D-Alanyl-D-Alanine dimers during peptidoglycan biosynthesis. D-cycloserine (DCS) is a D-Alanine analogue that targets peptidoglycan biosynthesis by inhibiting D-Alanine:D-Alanine ligase (Ddl). The VAN-DCS combination was found to be synergistic in VAN resistant S. aureus strains lacking van genes cluster. We hypothesize that this combination leads to opposite effects in S. aureus and enterococci strains harboring van genes cluster where VAN resistance is conferred by the synthesis of modified peptidoglycan precursors ending in D-Alanyl-D-Lactate. The calculated Fractional Inhibitory Concentration of VAN-DCS combination in a van- vancomycin-intermediate, VanA type, and VanB type strains were 0.5, 5 and 3, respectively. As a result, VAN-DCS combination leads to synergism in van-lacking strains, and to antagonism in strains harboring van genes cluster. The VAN-DCS antagonism is due to a mechanism that we named van-mediated Ddl inhibition bypass. Our results show that antibiotic combinations can lead to opposite effects depending on the genetic backgrounds. Vancomycin resistance genes cluster turns the outcome of vancomycin and D-cycloserine combination from synergism to antagonism.