A Convenient Chemoenzymatic Preparation of Chimeric Macrocyclic Peptide Antibiotics with Potent Activity against Gram-Negative Pathogens

Wood, Thomas M.; Slingerland, Cornelis J.; Martin, Nathaniel I.

doi:10.1021/acs.jmedchem.1c00176

Cited by 9 publications

(8 citation statements)

References 39 publications

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“…The synergists described in this section are specifically included on the basis of their OM-disrupting activity rather than a contribution of their inherent activity to synergy. We therefore do not include the combination of rifampicin with imipenem or trimethoprim, which is solely based on functional synergy. , In addition, we also do not cover reports describing systems where an OM-perturbing motif like PMBN is covalently linked to another antibiotic as a means of enhancing anti-Gram-negative activity. ,− …”

Section: Antibiotic-derived Synergistsmentioning

confidence: 99%

Synergy by Perturbing the Gram-Negative Outer Membrane: Opening the Door for Gram-Positive Specific Antibiotics

Wesseling

Martin

2022

ACS Infect. Dis.

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New approaches to target antibacterial agents toward Gram-negative bacteria are key, given the rise of antibiotic resistance. Since the discovery of polymyxin B nonapeptide as a potent Gram-negative outer membrane (OM)-permeabilizing synergist in the early 1980s, a vast amount of literature on such synergists has been published. This Review addresses a range of peptide-based and small organic compounds that disrupt the OM to elicit a synergistic effect with antibiotics that are otherwise inactive toward Gram-negative bacteria, with synergy defined as a fractional inhibitory concentration index (FICI) of <0.5. Another requirement for the inclusion of the synergists here covered is their potentiation of a specific set of clinically used antibiotics: erythromycin, rifampicin, novobiocin, or vancomycin. In addition, we have focused on those synergists with reported activity against Gram-negative members of the ESKAPE family of pathogens namely, Escherichia coli , Pseudomonas aeruginosa , Klebsiella pneumoniae , and/or Acinetobacter baumannii . In cases where the FICI values were not directly reported in the primary literature but could be calculated from the published data, we have done so, allowing for more direct comparison of potency with other synergists. We also address the hemolytic activity of the various OM-disrupting synergists reported in the literature, an effect that is often downplayed but is of key importance in assessing the selectivity of such compounds for Gram-negative bacteria.

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Section: Antibiotic-derived Synergistsmentioning

confidence: 99%

Synergy by Perturbing the Gram-Negative Outer Membrane: Opening the Door for Gram-Positive Specific Antibiotics

Wesseling

Martin

2022

ACS Infect. Dis.

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“…coli) that belong to the ESKAPE group of highly virulent pathogens . Moreover, newly developed antibiotics often affect already established targets and therefore suffer analogous drawbacks. , Thus, there is a need for antibiotics that act via novel modes of action and address new targets. − Here, the inhibition of bacterial cell division has moved into the focus of antibiotic research. Central to cell division is the divisome, , a dynamic complex composed of numerous membrane-associated proteins that assemble at the midcell plane to regulate cell constriction, peptidoglycan synthesis, and cell separation.…”

Section: Introductionmentioning

confidence: 99%

Covalent Proteomimetic Inhibitor of the Bacterial FtsQB Divisome Complex

et al. 2022

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The use of antibiotics is threatened by the emergence and spread of multidrug-resistant strains of bacteria. Thus, there is a need to develop antibiotics that address new targets. In this respect, the bacterial divisome, a multi-protein complex central to cell division, represents a potentially attractive target. Of particular interest is the FtsQB subcomplex that plays a decisive role in divisome assembly and peptidoglycan biogenesis in E. coli . Here, we report the structure-based design of a macrocyclic covalent inhibitor derived from a periplasmic region of FtsB that mediates its binding to FtsQ. The bioactive conformation of this motif was stabilized by a customized cross-link resulting in a tertiary structure mimetic with increased affinity for FtsQ. To increase activity, a covalent handle was incorporated, providing an inhibitor that impedes the interaction between FtsQ and FtsB irreversibly. The covalent inhibitor reduced the growth of an outer membrane-permeable E. coli strain, concurrent with the expected loss of FtsB localization, and also affected the infection of zebrafish larvae by a clinical E. coli strain. This first-in-class inhibitor of a divisome protein–protein interaction highlights the potential of proteomimetic molecules as inhibitors of challenging targets. In particular, the covalent mode-of-action can serve as an inspiration for future antibiotics that target protein–protein interactions.

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“…The peptides CPA and MHM were prepared using Fmoc solid phase peptide synthesis (SPPS) as described before. 24 CATH-2 was synthesized by Fmoc-chemistry at China Peptides (CPC scientific, Sunnyvale, CA). Stock solutions of peptides (2.5 mM CPA and 1.6 mM other peptides) were prepared in distilled water (or for CPA in 2% DMSO, 0.002% tween-20) and further diluted in appropriate medium as indicated in those assays.…”

Section: ■ Methodsmentioning

confidence: 99%

Chimeric Peptidomimetic Antibiotic Efficiently Neutralizes Lipopolysaccharides (LPS) and Bacteria-Induced Activation of RAW Macrophages

et al. 2023

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Peptide antibiotics have gathered attention given the urgent need to discover antimicrobials with new mechanisms of action. Their extended role as immunomodulators makes them interesting candidates for the development of compounds with dual mode of action. The objective of this study was to test the antiinflammatory capacity of a recently reported chimeric peptidomimetic antibiotic (CPA) composed of polymyxin B nonapeptide (PMBN) and a macrocyclic β-hairpin motif (MHM). We investigated the potential of CPA to inhibit lipopolysaccharide (LPS)-induced activation of RAW264.7 macrophages. In addition, we elucidated which structural motif was responsible for this activity by testing CPA, its building blocks, and their parent compounds separately. CPA showed excellent LPS neutralizing activity for both smooth and rough LPSs. At nanomolar concentrations, CPA completely inhibited LPS-induced nitric oxide, TNF-α, and IL-10 secretion. Murepavadin, MHM, and PMBN were incapable of neutralizing LPS in this assay, while PMB was less active compared to CPA. Isothermal titration calorimetry showed strong binding between the CPA and LPS with similar binding characteristics also found for the other compounds, indicating that binding does not necessarily correlate with neutralization of LPS. Finally, we showed that CPA-killed bacteria caused significantly less macrophage activation than bacteria killed with gentamicin, heat, or any of the other compounds. This indicates that the combined killing activity and LPS neutralization of CPA can prevent unwanted inflammation, which could be a major advantage over conventional antibiotics. Our data suggests that immunomodulatory activity can further strengthen the therapeutic potential of peptide antibiotics and should be included in the characterization of novel compounds.

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A Convenient Chemoenzymatic Preparation of Chimeric Macrocyclic Peptide Antibiotics with Potent Activity against Gram-Negative Pathogens

Cited by 9 publications

References 39 publications

Synergy by Perturbing the Gram-Negative Outer Membrane: Opening the Door for Gram-Positive Specific Antibiotics

Synergy by Perturbing the Gram-Negative Outer Membrane: Opening the Door for Gram-Positive Specific Antibiotics

Covalent Proteomimetic Inhibitor of the Bacterial FtsQB Divisome Complex

Chimeric Peptidomimetic Antibiotic Efficiently Neutralizes Lipopolysaccharides (LPS) and Bacteria-Induced Activation of RAW Macrophages

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