The mcr-1 gene can be disseminated via multiple mobile elements including Tn6330, its circular intermediate and plasmids harbouring such elements. It is often co-transmitted with other resistance determinants through IncHI2 plasmids. The functional mechanism of Tn6330, a typical composite transposon harbouring mcr-1, should be further investigated.
Staphylococcus aureus is a bacterial pathogen that causes food poisoning, various infections, and sepsis. Effective strategies and new drugs are needed to control S. aureus associated infections due to the emergence and rapid dissemination of antibiotic resistance. In the present study, the antibacterial activity, potential mode of action, and applications of flavonoids from licorice were investigated. Here, we showed that glabrol, licochalcone A, licochalcone C, and licochalcone E displayed high efficiency against methicillin-resistant Staphylococcus aureus (MRSA). Glabrol, licochalcone A, licochalcone C, and licochalcone E exhibited low cytotoxicity without hemolytic activity based on safety evaluation. Glabrol displayed rapid bactericidal activity with low levels of resistance development in vitro. Meanwhile, glabrol rapidly increased bacterial membrane permeability and dissipated the proton move force. Furthermore, we found that peptidoglycan, phosphatidylglycerol, and cardiolipin inhibited the antibacterial activity of glabrol. Molecular docking showed that glabrol binds to phosphatidylglycerol and cardiolipin through the formation of hydrogen bonds. Lastly, glabrol showed antibacterial activity against MRSA in both in vivo and in vitro models. Altogether, these results suggest that glabrol is a promising lead compound for the design of membrane-active antibacterial agents against MRSA and can be used as a disinfectant candidate as well.
MCR-1 is a phosphoethanolamine (pEtN) transferase that modifies the pEtN moiety of lipid A, conferring resistance to colistin, which is an antibiotic belonging to the class of polypeptide antibiotics known as polymyxins and is the last-line antibiotic used to treat multidrug resistant bacterial infections. Here we determined the crystal structure of the catalytic domain of MCR-1 (MCR-1-ED), which is originated in Escherichia coli (E. coli). MCR-1-ED was found to comprise several classical β-α-β-α motifs that constitute a “sandwich” conformation. Two interlaced molecules with different phosphorylation status of the residue T285 could give rise to two functional statuses of MCR-1 depending on the physiological conditions. MCR-1, like other known pEtN transferases, possesses an enzymatic site equipped with zinc binding residues. Interestingly, two zinc ions were found to mediate intermolecular interactions between MCR-1-ED molecules in one asymmetric unit and hence concatenation of MCR-1, allowing the protein to be oligomer. Findings of this work shall provide important insight into development of effective and clinically useful inhibitors of MCR-1 or structurally similar enzymes.
Staphylococcus aureus is one of the most important pathogens in humans and animals. The formation of biofilm by S. aureus is considered an important mechanism of antimicrobial resistance. Therefore, finding effective drugs against the biofilm produced by S. aureus has been a high priority. Licochalcone A (LAA), a natural plant product, was reported to have antibacterial activities and showed good activity against all 21 tested strains of S. aureus biofilm and planktonic cells. To detect the possible molecular mechanism of LAA against S. aureus biofilm or planktonic cells, Affymetrix GeneChips were used to determine the global comparative transcription of S. aureus biofilm and planktonic cells triggered by treatment with sub-bactericidal and sub-inhibitory concentrations of LAA, respectively. LAA significantly altered (greater than a 2- or less than -2-fold change) the expression of 693 genes in planktonic cells and 817 genes in biofilm. The levels of genes encoding autolysis-associated proteins, cell wall proteins, pathogenic factors, protein synthesis genes, and enzymes involved in capsule synthesis were significantly altered in LAA-treated S. aureus. Furthermore, some differences observed in the microarray analysis were verified by real-time RT-PCR. To our knowledge, this is the first observation of phenotype and expression profiles of S. aureus biofilm and planktonic cells in response to LAA treatment.
BackgroundSeveral retrospective studies have confirmed that video-assisted thoracoscopic surgery (VATS) following neoadjuvant chemotherapy is a safe and feasible treatment for advanced non-small cell lung cancer patients. As a minimally invasive technique, VATS usually leads to better clinical outcomes and better compliance with adjuvant treatment than conventional thoracotomy. Uniportal VATS (U-VATS) as an alternative option to conventional multi-port VATS has attracted much attention recently because reduced number and size of incisions may help to decrease inflammatory response and reduce postoperative pain for patients. However, rarely studies have reported the application of U-VATS following neoadjuvant chemotherapy for the treatment of advanced lung cancer patients.MethodsA total of 29 lung cancer patients undergoing VATS following neoadjuvant chemotherapy were included in this study. The clinical data of these patients were retrospectively analyzed, including the preoperative neoadjuvant chemotherapy plan, surgical effect, postoperative complications, operation time, operative blood loss, number of lymph nodes dissected and postoperative mortality.ResultsAll patients underwent VATS following two cycles of neoadjuvant chemotherapy. Among these patients, 26 completed U-VATS, two were converted to triple-port VATS, and one was converted to open thoracotomy. The operation time ranged from 120 min to 300 min (mean: 160 ± 38.5 min); the operative blood loss was 50–500 ml (mean:167.8 ± 78.4 ml); the number of lymph nodes dissected was 16–28 (mean: 21.9 ± 3.7); the postoperative drainage time was 3–13 d (mean: 5.6 ± 1.9 d); and the postoperative hospital stay was 6–16 d (7.7 ± 1.9 d). Postoperative complications occurred in five (17.2%) patients, including three cases of respiratory infection, one case of air leakage (more than two weeks), and one case of wound infection. In addition, the 30- and 90-day postoperative mortality was zero.ConclusionU-VATS following neoadjuvant chemotherapy is feasible and safe for the treatment of advanced lung cancer patients.
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