A Peptidomimetic Antibiotic Targets Outer Membrane Proteins and Disrupts Selectively the Outer Membrane in Escherichia coli

Urfer, Matthias; Bogdanović, Jasmina; Monte, Fabio Lo; Moehle, Kerstin; Zerbe, Katja; Omasits, Ulrich; Ahrens, Christian H.; Pessi, Gabriella; Eberl, Leo; Robinson, John A.

doi:10.1074/jbc.m115.691725

Cited by 94 publications

(92 citation statements)

References 76 publications

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“…Future work will therefore be orientated toward unraveling the threedimensional interaction of LlpA and BamA, in order to understand the nature of their protein-protein interaction. The direct interference with an essential protein(s) in the outer membrane, such as the BAM complex, is currently being explored as a novel antimicrobial strategy, for example, by designing peptides that actively interfere with the BAM machinery (71, 72) or peptidomimetics that selectively target ␤-barrel outer membrane proteins (73).…”

Section: Discussionmentioning

confidence: 99%

Hitting with a BAM: Selective Killing by Lectin-Like Bacteriocins

Ghequire

Swings

Michiels

et al. 2018

mBio

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Lectin-like bacteriocins (LlpAs) are secreted by proteobacteria and selectively kill strains of their own or related species, and they are composed of two B-lectin domains with divergent sequences. In spp., initial binding of these antibacterial proteins to cells is mediated by the carboxy-terminal domain through d-rhamnose residues present in the common polysaccharide antigen of their lipopolysaccharide, whereas the amino-terminal domain accounts for strain selectivity of killing. Here, we show that spontaneous LlpA-resistant mutants carry mutations in one of three surface-exposed moieties of the essential β-barrel outer membrane protein insertase BamA, the core component of the BAM complex. Polymorphism of this loop in different groups is linked to LlpA susceptibility, and targeted cells all share the same signature motif in this loop. Since heterologous expression of such a gene confers LlpA susceptibility upon a resistant strain, BamA represents the primary bacteriocin selectivity determinant in pseudomonads. Contrary to modular bacteriocins that require uptake via the Tol or Ton system, parasitism of BamA as an LlpA receptor advocates a novel bacteriocin killing mechanism initiated by impairment of the BAM machinery. Bacteria secrete a variety of molecules to eliminate microbial rivals. Bacteriocins are a pivotal group of peptides and proteins that assist in this fight, specifically killing related bacteria. In Gram-negative bacteria, these antibacterial proteins often comprise distinct domains for initial binding to a target cell's surface and subsequent killing via enzymatic or pore-forming activity. Here, we show that lectin-like bacteriocins, a family of bacteriocins that lack the prototypical modular toxin architecture, also stand out by parasitizing BamA, the core component of the outer membrane protein assembly machinery. A particular surface-exposed loop of BamA, critical for its function, serves as a key discriminant for cellular recognition, and polymorphisms in this loop determine whether a strain is susceptible or immune to a particular bacteriocin. These findings suggest a novel mechanism of contact-dependent killing that does not require cellular uptake. The evolutionary advantage of piracy of an essential cellular compound is highlighted by the observation that contact-dependent growth inhibition, a distinct antagonistic system, can equally take advantage of this receptor.

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Section: Discussionmentioning

confidence: 99%

Hitting with a BAM: Selective Killing by Lectin-Like Bacteriocins

Ghequire

Swings

Michiels

et al. 2018

mBio

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“…Secondly, the inhibitor of the CdiAB contact-inhibition system binds to BamA in a species-specific recognition that thereafter prevents cell growth and division (Aoki et al, 2008). Thirdly, a peptidomimetic compound designed to mimic natural defensin-like molecules binds BamA and inhibits growth of E. coli (Urfer et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

An investigation into the Omp85 protein BamK in hypervirulent Klebsiella pneumoniae, and its role in outer membrane biogenesis

Torres

Heinz

Stubenrauch

et al. 2018

Molecular Microbiology

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Members of the Omp85 protein superfamily have important roles in Gram-negative bacteria, with the archetypal protein BamA being ubiquitous given its essential function in the assembly of outer membrane proteins. In some bacterial lineages, additional members of the family exist and, in most of these cases, the function of the protein is unknown. We detected one of these Omp85 proteins in the pathogen Klebsiella pneumoniae B5055, and refer to the protein as BamK. Here, we show that bamK is a conserved element in the core genome of Klebsiella, and its expression rescues a loss-of-function ∆bamA mutant. We developed an E. coli model system to measure and compare the specific activity of BamA and BamK in the assembly reaction for the critical substrate LptD, and find that BamK is as efficient as BamA in assembling the native LptDE complex. Comparative structural analysis revealed that the major distinction between BamK and BamA is in the external facing surface of the protein, and we discuss how such changes may contribute to a mechanism for resistance against infection by bacteriophage.

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“…This outer membrane is a permeability barrier and tends to save the cell from the various external stresses and forces like the presence of antimicrobials. By interacting with the selected β-barrel outer membrane proteins including BamA and LptD, a novel macrocyclic peptide, JB-95, shows selective disruption of the outer cell membrane of the Gram negative bacteria 10,11,12 . Likewise, a target for removal of Pathogens is by targeting the bacterial protein secretion pathway.…”

Section: Issn: 2250-1177mentioning

confidence: 99%

Recent Promising Advances in Development of Antimicrobial Agents: A Review

Maqbool

Ishaq

2018

J. Drug Delivery Ther.

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Antimicrobial resistance is a serious global threat. There is a global menace of antibiotic resistant “super bug”, though the extent and the severity of the problem varies. Resistance hampers therapeutic options and drives clinicians to use newer and more expensive drugs. In serious cases, multi-resistance provides no treatment options. To overcome resistance, a continuous supply of new antibiotics offers an obvious way; but the pipeline of agents in development by the Pharmaceutical industry is very limited. There is an ever-evolving need to develop and evaluate newer alternative strategies for countering a worsening clinical situation to overcome resistance and reduce the morbidity and mortality associated with infections caused by antibiotic-resistant bacteria. The widespread distribution of Antimicrobial resistance has not been paralleled by the development of newer antimicrobials. This happens due to the process of drug discovery and clinical trials of new antimicrobials taking longer time and only a fewer new agents been approved for use. In modern era, where obstacles like chemo-resistance and mutations torment medicine, scientists across the world are looking to adapt lateral approaches in encountering diseases. Keywords: antimicrobial resistance, super bug, antibiotics

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A Peptidomimetic Antibiotic Targets Outer Membrane Proteins and Disrupts Selectively the Outer Membrane in Escherichia coli

Cited by 94 publications

References 76 publications

Hitting with a BAM: Selective Killing by Lectin-Like Bacteriocins

Hitting with a BAM: Selective Killing by Lectin-Like Bacteriocins

An investigation into the Omp85 protein BamK in hypervirulent Klebsiella pneumoniae, and its role in outer membrane biogenesis

Recent Promising Advances in Development of Antimicrobial Agents: A Review

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