Chimeric peptidomimetic antibiotics against Gram-negative bacteria.
Animals
Anti-Bacterial Agents
/ adverse effects
Bacterial Outer Membrane Proteins
/ chemistry
Biological Products
/ chemistry
Drug Discovery
Drug Resistance, Microbial
/ drug effects
Escherichia coli Proteins
/ chemistry
Fluorescence
Gram-Negative Bacteria
/ drug effects
Humans
Lipopolysaccharides
/ chemistry
Macrocyclic Compounds
/ adverse effects
Male
Mice
Microbial Sensitivity Tests
Microbial Viability
/ drug effects
Microscopy, Electron, Transmission
Models, Molecular
Mutation
Peptidomimetics
/ adverse effects
Photoaffinity Labels
Journal
Nature
ISSN: 1476-4687
Titre abrégé: Nature
Pays: England
ID NLM: 0410462
Informations de publication
Date de publication:
12 2019
12 2019
Historique:
received:
08
08
2018
accepted:
13
08
2019
pubmed:
28
10
2019
medline:
28
4
2020
entrez:
25
10
2019
Statut:
ppublish
Résumé
There is an urgent need for new antibiotics against Gram-negative pathogens that are resistant to carbapenem and third-generation cephalosporins, against which antibiotics of last resort have lost most of their efficacy. Here we describe a class of synthetic antibiotics inspired by scaffolds derived from natural products. These chimeric antibiotics contain a β-hairpin peptide macrocycle linked to the macrocycle found in the polymyxin and colistin family of natural products. They are bactericidal and have a mechanism of action that involves binding to both lipopolysaccharide and the main component (BamA) of the β-barrel folding complex (BAM) that is required for the folding and insertion of β-barrel proteins into the outer membrane of Gram-negative bacteria. Extensively optimized derivatives show potent activity against multidrug-resistant pathogens, including all of the Gram-negative members of the ESKAPE pathogens
Identifiants
pubmed: 31645764
doi: 10.1038/s41586-019-1665-6
pii: 10.1038/s41586-019-1665-6
doi:
Substances chimiques
Anti-Bacterial Agents
0
Bacterial Outer Membrane Proteins
0
BamA protein, E coli
0
Biological Products
0
Escherichia coli Proteins
0
Lipopolysaccharides
0
Macrocyclic Compounds
0
Peptidomimetics
0
Photoaffinity Labels
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
452-458Subventions
Organisme : Wellcome Trust
ID : 202728/Z/16/Z
Pays : United Kingdom
Commentaires et corrections
Type : ErratumIn
Type : CommentIn
Références
WHO. Global Priority List of Antibiotic-resistant Bacteria to Guide Research, Discovery, and Development of New Antibiotics (World Health Organization, Geneva, 2017).
Boucher, H. W. et al. Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin. Infect. Dis. 48, 1–12 (2009).
doi: 10.1086/595011
O’Neill, J. Project Syndicate – A Call to Antimicrobial Arms https://www.project-syndicate.org/commentary/antibiotics-resistance-economic-costs-by-jim-o-neill-2015-02 (2015).
Paterson, D. L. & Harris, P. N. A. Colistin resistance: a major breach in our last line of defence. Lancet Infect. Dis. 16, 132–133 (2016).
doi: 10.1016/S1473-3099(15)00463-6
Henderson, J. C. et al. The power of asymmetry: architecture and assembly of the Gram-negative outer membrane bilayer. Annu. Rev. Microbiol. 70, 255–278 (2016).
doi: 10.1146/annurev-micro-102215-095308
Konovalova, A., Kahne, D. E. & Silhavy, T. J. Outer membrane biogenesis. Annu. Rev. Microbiol. 71, 539–556 (2017).
doi: 10.1146/annurev-micro-090816-093754
Srinivas, N. et al. Peptidomimetic antibiotics target outer-membrane biogenesis in Pseudomonas aeruginosa. Science 327, 1010–1013 (2010).
doi: 10.1126/science.1182749
Werneburg, M. et al. Inhibition of lipopolysaccharide transport to the outer membrane in Pseudomonas aeruginosa by peptidomimetic antibiotics. ChemBioChem 13, 1767–1775 (2012).
doi: 10.1002/cbic.201200276
Noinaj, N., Rollauer, S. E. & Buchanan, S. K. The β-barrel membrane protein insertase machinery from Gram-negative bacteria. Curr. Opin. Struct. Biol. 31, 35–42 (2015).
doi: 10.1016/j.sbi.2015.02.012
Storm, D. R., Rosenthal, K. S. & Swanson, P. E. Polymyxin and related peptide antibiotics. Annu. Rev. Biochem. 46, 723–763 (1977).
doi: 10.1146/annurev.bi.46.070177.003451
Mares, J., Kumaran, S., Gobbo, M. & Zerbe, O. Interactions of lipopolysaccharide and polymyxin studied by NMR spectroscopy. J. Biol. Chem. 284, 11498–11506 (2009).
doi: 10.1074/jbc.M806587200
Roberts, K. D. et al. Antimicrobial activity and toxicity of the major lipopeptide components of polymyxin B and colistin: last-line antibiotics against multidrug-resistant Gram-negative bacteria. ACS Infect. Dis. 1, 568–575 (2015).
doi: 10.1021/acsinfecdis.5b00085
Baron, S., Hadjadj, L., Rolain, J.-M. & Olaitan, A. O. Molecular mechanisms of polymyxin resistance: knowns and unknowns. Int. J. Antimicrob. Agents 48, 583–591 (2016).
doi: 10.1016/j.ijantimicag.2016.06.023
Olaitan, A. O., Morand, S. & Rolain, J.-M. Mechanisms of polymyxin resistance: acquired and intrinsic resistance in bacteria. Front. Microbiol. 5, 643 (2014).
doi: 10.3389/fmicb.2014.00643
Raetz, C. R., Reynolds, C. M., Trent, M. S. & Bishop, R. E. Lipid A modification systems in Gram-negative bacteria. Annu. Rev. Biochem. 76, 295–329 (2007).
doi: 10.1146/annurev.biochem.76.010307.145803
Groisman, E. A. The pleiotropic two-component regulatory system PhoP–PhoQ. J. Bacteriol. 183, 1835–1842 (2001).
doi: 10.1128/JB.183.6.1835-1842.2001
McPhee, J. B., Lewenza, S. & Hancock, R. E. Cationic antimicrobial peptides activate a two-component regulatory system, PmrA–PmrB, that regulates resistance to polymyxin B and cationic antimicrobial peptides in Pseudomonas aeruginosa. Mol. Microbiol. 50, 205–217 (2003).
doi: 10.1046/j.1365-2958.2003.03673.x
Okuda, S., Sherman, D. J., Silhavy, T. J., Ruiz, N. & Kahne, D. Lipopolysaccharide transport and assembly at the outer membrane: the PEZ model. Nat. Rev. Microbiol. 14, 337–345 (2016).
doi: 10.1038/nrmicro.2016.25
Hartmann, J.-B., Zahn, M., Burmann, I. M., Bibow, S. & Hiller, S. Sequence-specific solution NMR assignments of the β-barrel insertase BamA to monitor its conformational ensemble at the atomic level. J. Am. Chem. Soc. 140, 11252–11260 (2018).
doi: 10.1021/jacs.8b03220
Mahoney, T. F., Ricci, D. P. & Silhavy, T. J. Classifying β-barrel assembly substrates by manipulating essential Bam complex members. J. Bacteriol. 198, 1984–1992 (2016).
doi: 10.1128/JB.00263-16
Lee, J. et al. Characterization of a stalled complex on the β-barrel assembly machine. Proc. Natl Acad. Sci. USA 113, 8717–8722 (2016).
doi: 10.1073/pnas.1604100113
Gunasinghe, S. D. et al. The WD40 protein BamB mediates coupling of BAM complexes into assembly precincts in the bacterial outer membrane. Cell Rep. 23, 2782–2794 (2018).
doi: 10.1016/j.celrep.2018.04.093
Mitchell, A. M. & Silhavy, T. J. Envelope stress responses: balancing damage repair and toxicity. Nat. Rev. Microbiol. 17, 417–428 (2019).
doi: 10.1038/s41579-019-0199-0
Storek, K. M. et al. Monoclonal antibody targeting the β-barrel assembly machine of Escherichia coli is bactericidal. Proc. Natl Acad. Sci. USA 115, 3692–3697 (2018).
doi: 10.1073/pnas.1800043115
Browning, D. F. et al. Mutational and topological analysis of the Escherichia coli BamA protein. PLoS ONE 8, e84512 (2013).
doi: 10.1371/journal.pone.0084512
Lee, J. et al. Substrate binding to BamD triggers a conformational change in BamA to control membrane insertion. Proc. Natl Acad. Sci. USA 115, 2359–2364 (2018).
doi: 10.1073/pnas.1711727115
Rigel, N. W., Ricci, D. P. & Silhavy, T. J. Conformation-specific labeling of BamA and suppressor analysis suggest a cyclic mechanism for β-barrel assembly in Escherichia coli. Proc. Natl Acad. Sci. USA 110, 5151–5156 (2013).
doi: 10.1073/pnas.1302662110
Dixon, R. A. & Chopra, I. Polymyxin B and polymyxin B nonapeptide alter cytoplasmic membrane permeability in Escherichia coli. J. Antimicrob. Chemother. 18, 557–563 (1986).
doi: 10.1093/jac/18.5.557
Moffatt, J. H. et al. Colistin resistance in Acinetobacter baumannii is mediated by complete loss of lipopolysaccharide production. Antimicrob. Agents Chemother. 54, 4971–4977 (2010).
doi: 10.1128/AAC.00834-10
Choi, M. et al. MSstats: an R package for statistical analysis of quantitative mass spectrometry-based proteomic experiments. Bioinformatics 30, 2524–2526 (2014).
doi: 10.1093/bioinformatics/btu305
Carlson, M. UniProt.ws: R interface to UniProt web services. R package version 2.14.0. https://bioconductor.org/packages/release/bioc/html/UniProt.ws.html (2018)