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      Outer-membrane-acting peptides and lipid II-targeting antibiotics cooperatively kill Gram-negative pathogens

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          Abstract

          The development and dissemination of antibiotic-resistant bacterial pathogens is a growing global threat to public health. Novel compounds and/or therapeutic strategies are required to face the challenge posed, in particular, by Gram-negative bacteria. Here we assess the combined effect of potent cell-wall synthesis inhibitors with either natural or synthetic peptides that can act on the outer-membrane. Thus, several linear peptides, either alone or combined with vancomycin or nisin, were tested against selected Gram-negative pathogens, and the best one was improved by further engineering. Finally, peptide D-11 and vancomycin displayed a potent antimicrobial activity at low μM concentrations against a panel of relevant Gram-negative pathogens. This combination was highly active in biological fluids like blood, but was non-hemolytic and non-toxic against cell lines. We conclude that vancomycin and D-11 are safe at >50-fold their MICs. Based on the results obtained, and as a proof of concept for the newly observed synergy, a Pseudomonas aeruginosa mouse infection model experiment was also performed, showing a 4 log 10 reduction of the pathogen after treatment with the combination. This approach offers a potent alternative strategy to fight (drug-resistant) Gram-negative pathogens in humans and mammals.

          Abstract

          Li, Cebrian et al. show that a combination of peptide D-11 and vancomycin exhibits a potent antimicrobial activity against a panel of Gram-negative pathogens without apparent toxicity. They find that this combination is also effective in clearing Pseudomonas aeruginosa in mice, providing a potential antimicrobial therapy for humans.

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          Most cited references63

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          Synergy, antagonism, and what the chequerboard puts between them.

          F C Odds (2003)
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            Antibacterial drug discovery in the resistance era.

            The looming antibiotic-resistance crisis has penetrated the consciousness of clinicians, researchers, policymakers, politicians and the public at large. The evolution and widespread distribution of antibiotic-resistance elements in bacterial pathogens has made diseases that were once easily treatable deadly again. Unfortunately, accompanying the rise in global resistance is a failure in antibacterial drug discovery. Lessons from the history of antibiotic discovery and fresh understanding of antibiotic action and the cell biology of microorganisms have the potential to deliver twenty-first century medicines that are able to control infection in the resistance era.
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              Mechanisms of Antimicrobial Resistance in ESKAPE Pathogens

              The ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) are the leading cause of nosocomial infections throughout the world. Most of them are multidrug resistant isolates, which is one of the greatest challenges in clinical practice. Multidrug resistance is amongst the top three threats to global public health and is usually caused by excessive drug usage or prescription, inappropriate use of antimicrobials, and substandard pharmaceuticals. Understanding the resistance mechanisms of these bacteria is crucial for the development of novel antimicrobial agents or other alternative tools to combat these public health challenges. Greater mechanistic understanding would also aid in the prediction of underlying or even unknown mechanisms of resistance, which could be applied to other emerging multidrug resistant pathogens. In this review, we summarize the known antimicrobial resistance mechanisms of ESKAPE pathogens.
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                Author and article information

                Contributors
                o.p.kuipers@rug.nl
                Journal
                Commun Biol
                Commun Biol
                Communications Biology
                Nature Publishing Group UK (London )
                2399-3642
                4 January 2021
                4 January 2021
                2021
                : 4
                Affiliations
                [1 ]GRID grid.4830.f, ISNI 0000 0004 0407 1981, Department of Molecular Genetics, , Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, ; Nijenborgh 7, 9747AG Groningen, The Netherlands
                [2 ]GRID grid.216938.7, ISNI 0000 0000 9878 7032, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Molecular Microbiology and Technology of the Ministry of Education, Department of Microbiology, College of Life Sciences, , Nankai University, ; 30071 Tianjin, China
                [3 ]GRID grid.34418.3a, ISNI 0000 0001 0727 9022, Present Address: State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, Hubei Key Laboratory of Industrial Biotechnology, School of Life Sciences, , Hubei University, ; 430062 Wuhan, China
                [4 ]GRID grid.4489.1, ISNI 0000000121678994, Present Address: Department of Microbiology, Faculty of Sciences, , University of Granada, ; Av. Fuentenueva s/n, 18071 Granada, Spain
                Article
                1511
                10.1038/s42003-020-01511-1
                7782785
                33398076
                e97451c3-8dce-4216-95f9-da67432844a8
                © The Author(s) 2021

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                Funding
                Funded by: FundRef https://doi.org/10.13039/501100010902, National Science Foundation of China | Joint Research Fund for Overseas Chinese Scholars and Scholars in Hong Kong and Macao;
                Funded by: FundRef https://doi.org/10.13039/501100003246, Nederlandse Organisatie voor Wetenschappelijk Onderzoek (Netherlands Organisation for Scientific Research);
                Categories
                Article
                Custom metadata
                © The Author(s) 2021

                antimicrobial resistance,antibiotics
                antimicrobial resistance, antibiotics

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