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      A new antibiotic kills pathogens without detectable resistance

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          Abstract

          Antibiotic resistance is spreading faster than the introduction of new compounds into clinical practice, causing a public health crisis. Most antibiotics were produced by screening soil microorganisms, but this limited resource of cultivable bacteria was overmined by the 1960s. Synthetic approaches to produce antibiotics have been unable to replace this platform. Uncultured bacteria make up approximately 99% of all species in external environments, and are an untapped source of new antibiotics. We developed several methods to grow uncultured organisms by cultivation in situ or by using specific growth factors. Here we report a new antibiotic that we term teixobactin, discovered in a screen of uncultured bacteria. Teixobactin inhibits cell wall synthesis by binding to a highly conserved motif of lipid II (precursor of peptidoglycan) and lipid III (precursor of cell wall teichoic acid). We did not obtain any mutants of Staphylococcus aureus or Mycobacterium tuberculosis resistant to teixobactin. The properties of this compound suggest a path towards developing antibiotics that are likely to avoid development of resistance.

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          Drugs for bad bugs: confronting the challenges of antibacterial discovery.

          David J. Payne, Michael Gwynn, David Holmes … (2007)
          The sequencing of the first complete bacterial genome in 1995 heralded a new era of hope for antibacterial drug discoverers, who now had the tools to search entire genomes for new antibacterial targets. Several companies, including GlaxoSmithKline, moved back into the antibacterials area and embraced a genomics-derived, target-based approach to screen for new classes of drugs with novel modes of action. Here, we share our experience of evaluating more than 300 genes and 70 high-throughput screening campaigns over a period of 7 years, and look at what we learned and how that has influenced GlaxoSmithKline's antibacterials strategy going forward.
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            Digital DNA-DNA hybridization for microbial species delineation by means of genome-to-genome sequence comparison

            Alexander Auch, Mathias von Jan, Hans-Peter Klenk … (2010)
            The pragmatic species concept for Bacteria and Archaea is ultimately based on DNA-DNA hybridization (DDH). While enabling the taxonomist, in principle, to obtain an estimate of the overall similarity between the genomes of two strains, this technique is tedious and error-prone and cannot be used to incrementally build up a comparative database. Recent technological progress in the area of genome sequencing calls for bioinformatics methods to replace the wet-lab DDH by in-silico genome-to-genome comparison. Here we investigate state-of-the-art methods for inferring whole-genome distances in their ability to mimic DDH. Algorithms to efficiently determine high-scoring segment pairs or maximally unique matches perform well as a basis of inferring intergenomic distances. The examined distance functions, which are able to cope with heavily reduced genomes and repetitive sequence regions, outperform previously described ones regarding the correlation with and error ratios in emulating DDH. Simulation of incompletely sequenced genomes indicates that some distance formulas are very robust against missing fractions of genomic information. Digitally derived genome-to-genome distances show a better correlation with 16S rRNA gene sequence distances than DDH values. The future perspectives of genome-informed taxonomy are discussed, and the investigated methods are made available as a web service for genome-based species delineation.
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              Bacterial phylogeny structures soil resistomes across habitats

              Kevin J. Forsberg, Sanket Patel, Molly Gibson … (2014)
              Summary Ancient and diverse antibiotic resistance genes (ARGs) have previously been identified from soil 1–3 , including genes identical to those in human pathogens 4 . Despite the apparent overlap between soil and clinical resistomes 4–6 , factors influencing ARG composition in soil and their movement between genomes and habitats remain largely unknown 3 . General metagenome functions often correlate with the underlying structure of bacterial communities 7–12 . However, ARGs are hypothesized to be highly mobile 4,5,13 , prompting speculation that resistomes may not correlate with phylogenetic signatures or ecological divisions 13,14 . To investigate these relationships, we performed functional metagenomic selections for resistance to 18 antibiotics from 18 agricultural and grassland soils. The 2895 ARGs we discovered were predominantly novel, and represent all major resistance mechanisms 15 . We demonstrate that distinct soil types harbor distinct resistomes, and that nitrogen fertilizer amendments strongly influenced soil ARG content. Resistome composition also correlated with microbial phylogenetic and taxonomic structure, both across and within soil types. Consistent with this strong correlation, mobility elements syntenic with ARGs were rare in soil compared to sequenced pathogens, suggesting that ARGs in the soil may not transfer between bacteria as readily as is observed in the clinic. Together, our results indicate that bacterial community composition is the primary determinant of soil ARG content, challenging previous hypotheses that horizontal gene transfer effectively decouples resistomes from phylogeny 13,14 .
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 0410462
                Journal ID (pubmed-jr-id): 6011
                Journal ID (nlm-ta): Nature
                Journal ID (iso-abbrev): Nature
                Title: Nature
                ISSN (Print): 0028-0836
                ISSN (Electronic): 1476-4687
                Publication date Nihms-submitted: 23 July 2020
                Publication date (Electronic): 07 January 2015
                Publication date (Print): 22 January 2015
                Publication date PMC-release: 08 August 2020
                Volume: 517
                Issue: 7535
                Pages: 455-459
                Affiliations
                [1 ]NovoBiotic Pharmaceuticals, Cambridge, Massachusetts 02138, USA.
                [2 ]Institute of Medical Microbiology, Immunology and Parasitology—Pharmaceutical Microbiology Section, University of Bonn, Bonn 53115, Germany.
                [3 ]German Centre for Infection Research (DZIF), Partner Site Bonn-Cologne, 53115 Bonn, Germany.
                [4 ]Antimicrobial Discovery Center, Northeastern University, Department of Biology, Boston, Massachusetts 02115, USA.
                [5 ]Institute for Pharmaceutical Biology, University of Bonn, Bonn 53115, Germany.
                [6 ]Department of Biology, Northeastern University, Boston, Massachusetts 02115, USA.
                [7 ]Selcia, Ongar, Essex CM5 0GS, UK.
                Author notes

                Author Contributions K.L. and T.S. designed the study, analysed results, and wrote the paper. L.L.L. designed the study and analysed results. A.J.P. designed the study, performed compound isolation and structure determination and analysed data. B.P.C. designed the study, performed susceptibility experiments and wrote the paper. D.E.H. oversaw preclinical work including designing studies and analysing data. S.E. designed cultivation experiments and analysed data. M.J., L.L. and V.A.S. designed and performed experiments on structure determination and analysed data. I.E. and A.M. designed and performed experiments on mechanism of action. A.L.S., D.R.C., C.R.F., K.A.F., W.P.M., A.G.N., A.M.Z. and C.C. performed experiments on compound production, isolation, susceptibility testing and data analysis. T.F.S. identified the biosynthetic cluster.

                [*]

                These authors contributed equally to this work.

                Correspondence and requests for materials should be addressed to K.L. ( k.lewis@ 123456neu.edu ).
                Article
                Accession ID: PMC7414797 Pmcid ID: PMC7414797 Pmc-uid ID: 7414797 Manuscript ID: nihpa1613115
                DOI: 10.1038/nature14098
                PMC ID: 7414797
                PubMed ID: 25561178
                SO-VID: 43480773-ddf3-4a47-b60d-6869640cd35b
                License:

                Reprints and permissions information is available at www.nature.com/reprints.

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