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An Outer Membrane Protein-Targeting Antibiotic Against Resistant Gram-Negative Bacterial Pathogens

ABSTRACT: 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.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Escherichia Coli

SUBMITTER: Maik Müller

LAB HEAD: Bernd Wollscheid

PROVIDER: PXD010174 | Pride | 2019-10-22

REPOSITORIES: Pride

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Chimeric peptidomimetic antibiotics against Gram-negative bacteria.

Luther Anatol A Urfer Matthias M Zahn Michael M Müller Maik M Wang Shuang-Yan SY Mondal Milon M Vitale Alessandra A Hartmann Jean-Baptiste JB Sharpe Timothy T Monte Fabio Lo FL Kocherla Harsha H Cline Elizabeth E Pessi Gabriella G Rath Parthasarathi P Modaresi Seyed Majed SM Chiquet Petra P Stiegeler Sarah S Verbree Carolin C Remus Tobias T Schmitt Michel M Kolopp Caroline C Westwood Marie-Anne MA Desjonquères Nicolas N Brabet Emile E Hell Sophie S LePoupon Karen K Vermeulen Annie A Jaisson Régis R Rithié Virginie V Upert Grégory G Lederer Alexander A Zbinden Peter P Wach Achim A Moehle Kerstin K Zerbe Katja K Locher Hans H HH Bernardini Francesca F Dale Glenn E GE Eberl Leo L Wollscheid Bernd B Hiller Sebastian S Robinson John A JA Obrecht Daniel D

Nature 20191023 7787

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 ...[more]

PMID: 31645764

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Project description:Gram-negative bacteria possess stress responses to maintain the integrity of the cell envelope. Stress sensors monitor outer membrane permeability, envelope protein folding, and energization of the inner membrane. The systems used by Gram-negative bacteria to sense and combat stress resulting from disruption of the peptidoglycan layer are not well characterized. The peptidoglycan layer is a single molecule that completely surrounds the cell and ensures its structural integrity. During cell growth new peptidoglcyan subunits are incorporated into the peptidoglycan layer by a series of enzymes called the penicillin-binding proteins (PBPs). To explore how Gram-negative bacteria respond to peptidoglycan stress, global gene expression analysis was used to identify Escherichia coli stress responses activated following inhibition of specific PBPs by the Î²-lactam antibiotics mecillinam and cefsulodin. Inhibition of PBPs with different roles in peptidoglycan synthesis has different consequences for cell morphology and viability, suggesting that not all perturbations to the peptidoglycan layer generate equivalent stresses. We demonstrate that inhibition of different PBPs resulted in both shared and unique stress responses. The regulation of capsular synthesis (Rcs) phosphorelay was activated by inhibition of all of the PBPs tested. Furthermore, we show that activation of the Rcs phosphorelay increased survival in the presence of these antibiotics, independently of capsule synthesis. Both activation of the phosphorelay and survival required signal transduction via the outer membrane lipoprotein RcsF and the response regulator RcsB. We propose that the Rcs pathway responds to peptidoglycan damage and contributes to the intrinsic resistance of E. coli to Î²-lactam antibiotics. We used microarrays to identify changes in gene expression resulting from treatment of Escherichia coli with the Î²-lactam antibiotics cefsulodin, mecillinam, or the combination. This SuperSeries is composed of the following subset Series:; GSE10158: Expression of Escherichia coli treated with cefsulodin and mecillinam, alone and in combination; GSE10159: Expression of Escherichia coli treated with cefsulodin and mecillinam, alone at the minimum inhibitory concentration Experiment Overall Design: Refer to individual Series

Project description:Gram-negative bacteria possess stress responses to maintain the integrity of the cell envelope. Stress sensors monitor outer membrane permeability, envelope protein folding, and energization of the inner membrane. The systems used by Gram-negative bacteria to sense and combat stress resulting from disruption of the peptidoglycan layer are not well characterized. The peptidoglycan layer is a single molecule that completely surrounds the cell and ensures its structural integrity. During cell growth new peptidoglcyan subunits are incorporated into the peptidoglycan layer by a series of enzymes called the penicillin-binding proteins (PBPs). To explore how Gram-negative bacteria respond to peptidoglycan stress, global gene expression analysis was used to identify Escherichia coli stress responses activated following inhibition of specific PBPs by the Î²-lactam antibiotics mecillinam and cefsulodin. Inhibition of PBPs with different roles in peptidoglycan synthesis has different consequences for cell morphology and viability, suggesting that not all perturbations to the peptidoglycan layer generate equivalent stresses. We demonstrate that inhibition of different PBPs resulted in both shared and unique stress responses. The regulation of capsular synthesis (Rcs) phosphorelay was activated by inhibition of all of the PBPs tested. Furthermore, we show that activation of the Rcs phosphorelay increased survival in the presence of these antibiotics, independently of capsule synthesis. Both activation of the phosphorelay and survival required signal transduction via the outer membrane lipoprotein RcsF and the response regulator RcsB. We propose that the Rcs pathway responds to peptidoglycan damage and contributes to the intrinsic resistance of E. coli to Î²-lactam antibiotics. We used microarrays to identify changes in gene expression resulting from treatment of Escherichia coli with the Î²-lactam antibiotics cefsulodin, mecillinam, or the combination. Experiment Overall Design: E. coli was treated with two b-lactam antibiotics, cefsulodin and mecillinam, alone at the minimum inhibitory concentration to identify the expression changes in response to antibiotic-induced peptidoglycan stress. E. coli was grown to an OD of 0.2 at which time cefsulodin or mecillinam was added. Samples of the bacteria were collected at 5 and 10 minutes after treatment with cefsulodin and 60 minutes after treatment with mecillinam. Untreated cells were also collected at the same time points as controls. Three biological replicates were collected for all time points and samples, however, only one of the 5 minute untreated samples was hybridized to the arrays. In addition, a single sample from cells treated with the combination of cefsulodin and mecillinam was hybridized to allow for comparison with samples hybridized to Affymetrix antisense genechips.

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