There is an urgent need for novel antibiotics against carbapenem and 3rd generation cephalosporin-resistant Gram-negative pathogens, for which the last-resort antibiotics have lost most of their efficacy. We describe here a novel class of synthetic antibiotics that was inspired from natural product-derived scaffolds. The antibiotics have an unprecedented mechanism of action, which targets the main component (BamA) of the Bam folding machinery required for folding and insertion of ß-barrel proteins into the outer membrane of Gram-negative bacteria. This OMPTA (outer membrane protein-targeting antibiotic) class shows potent activity against multidrug-resistant Gram-negative ESKAPE pathogens and overcomes colistin-resistance both in vitro and in vivo. A clinical candidate has the potential to address life threatening Gram-negative infections with high unmet medical need.
[dataset license: CC0 1.0 Universal (CC0 1.0)]
Keywords: Gram-negative ESKAPE pathogens ; E.coli ; macrocyclic peptidomimetic antibiotics ; OMPTA (outer membrane-targeting antibiotics) ; Bam complex ; Lpt complex ; photo crosslinking ; photoaffinity labeling ; interaction mapping ; DDA ; LC-MS/MS ; Thermo Q-Exactive Plus ; novel molecular mode of action ; MassIVE.quant reviewed - Gold
Principal Investigators: (in alphabetical order) |
Bernd Wollscheid, Institute of Molecular Systems Biology & Department of Health Sciences and Technology, ETH Zurich, Switzerland, N/A |
Submitting User: | ccms |
Luther A, Urfer M, Zahn M, Müller M, Wang SY, Mondal M, Vitale A, Hartmann JB, Sharpe T, Monte FL, Kocherla H, Cline E, Pessi G, Rath P, Modaresi SM, Chiquet P, Stiegeler S, Verbree C, Remus T, Schmitt M, Kolopp C, Westwood MA, Desjonquères N, Brabet E, Hell S, LePoupon K, Vermeulen A, Jaisson R, Rithié V, Upert G, Lederer A, Zbinden P, Wach A, Moehle K, Zerbe K, Locher HH, Bernardini F, Dale GE, Eberl L, Wollscheid B, Hiller S, Robinson JA, Obrecht D.
Chimeric peptidomimetic antibiotics against Gram-negative bacteria.
Nature. 2019 Dec;576(7787):452-458. Epub 2019 Oct 23.
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