Modulators of protein–protein interactions as antimicrobial agents

Kahan, Rashi; Worm, Dennis J.; Castro, Guilherme Vieira de; Ng, Simon; Barnard, Anna

doi:10.1039/d0cb00205d

Cited by 24 publications

(23 citation statements)

References 181 publications

(307 reference statements)

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“…14 Therefore, disrupting existing PPIs or generating new ones to monitor or intervene in such processes is a major endeavour in peptide and protein design and engineering. [14][15][16] Nonetheless, even with bioactive polypeptides that target PPIs in hand, the challenge of delivering these into mammalian cells where they would be most useful remains. Exogenous reagents-usually proteins and larger assemblies-presented to cells can enter actively through endocytosis.…”

Section: Introductionmentioning

confidence: 99%

De novo designed peptides for cellular delivery and subcellular localisation

et al. 2022

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Increasingly, it is possible to design peptide and protein assemblies de novo from first principles or computationally. This provides new routes to functional synthetic polypeptides, including designs to target and bind proteins of interest. Much of this work has been developed in vitro. Therefore, a challenge is to deliver de novo polypeptides efficiently to sites of action within cells. Here, we describe the design, characterization, intracellular delivery, and subcellular localisation of a de novo synthetic peptide system. This comprises a dual-function basic peptide, programmed both for cell penetration and target binding, and a complementary acidic peptide that can be fused to proteins of interest and introduced into cells using synthetic DNA. The designs are characterized in vitro using biophysical methods and X-ray crystallography. The utility of the system for delivery into mammalian cells and subcellular targeting is demonstrated by marking organelles and actively engaging functional protein complexes.

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Section: Introductionmentioning

confidence: 99%

De novo designed peptides for cellular delivery and subcellular localisation

et al. 2022

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“…Bacterial protein–protein interactions (PPIs) are involved in a multitude of vital cellular processes and are hence increasingly being investigated as antibiotic targets to tackle the exacerbating problem of antimicrobial resistance. , One family of PPIs that are abundant in prokaryotes but remain significantly underexplored as therapeutic targets are type II toxin-antitoxin (TA) modules . These systems consist of toxin and antitoxin proteins that form a tight PPI .…”

Section: Introductionmentioning

confidence: 99%

Characterization of the Key Determinants of Phd Antitoxin Mediated Doc Toxin Inactivation in Salmonella

et al. 2022

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In the search for novel antimicrobial therapeutics, toxin-antitoxin (TA) modules are promising yet underexplored targets for overcoming antibiotic failure. The bacterial toxin Doc has been associated with the persistence of Salmonella in macrophages, enabling its survival upon antibiotic exposure. After developing a novel method to produce the recombinant toxin, we have used antitoxin-mimicking peptides to thoroughly investigate the mechanism by which its cognate antitoxin Phd neutralizes the activity of Doc. We reveal insights into the molecular detail of the Phd–Doc relationship and discriminate antitoxin residues that stabilize the TA complex from those essential for inhibiting the activity of the toxin. Coexpression of Doc and antitoxin peptides in Salmonella was able to counteract the activity of the toxin, confirming our in vitro results with equivalent sequences. Our findings provide key principles for the development of chemical tools to study and therapeutically interrogate this important class of protein–protein interactions.

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“…The emergence of multidrug resistance to current antibiotics among pathogens highlights the importance of the discovery of novel antimicrobials with minimized antimicrobial resistance. Protein-protein interactions (PPI) are appropriate targets for reducing antimicrobial resistance [10]. We focused on the specific and conserved bacterial PPIs for antimicrobial discovery [11].…”

Section: Introductionmentioning

confidence: 99%

“…antimicrobial resistance [10]. We focused on the specific and conserved bacterial PPIs for antimicrobial discovery [11].…”

Section: Introductionmentioning

confidence: 99%

QSAR, Docking, and Molecular Dynamics Simulation Studies of Sigmacidins as Antimicrobials against Streptococci

Yang

2022

IJMS

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Streptococci are a family of bacterial species significantly affecting human health. In addition, environmental Streptococci represent one of the major causes of diverse livestock diseases. Due to antimicrobial resistance, there is an urgent need for novel antimicrobial agent discovery against Streptococci. We discovered a class of benzoic acid derivatives named sigmacidins inhibiting the bacterial RNA polymerase-σ factor interaction and demonstrating excellent antimicrobial activity against Streptococci. In this work, a combinational computer approach was applied to gain insight into the structural basis and mechanism of action of sigmacidins as antimicrobials against Streptococcus pneumoniae. Both two- and three-dimensional quantitative structure-active relationships (2D and 3D QSAR) of sigmacidins displayed good predictive ability. Moreover, molecular docking and molecular dynamics simulation studies disclosed possible contacts between the inhibitors and the protein. The results obtained in this study provided understanding and new directions to the further optimizations of sigmacidins as novel antimicrobials.

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Modulators of protein–protein interactions as antimicrobial agents

Abstract: This review describes recent efforts towards the modulation of protein–protein interactions in infectious bacteria.

Cited by 24 publications

References 181 publications

De novo designed peptides for cellular delivery and subcellular localisation

De novo designed peptides for cellular delivery and subcellular localisation

Characterization of the Key Determinants of Phd Antitoxin Mediated Doc Toxin Inactivation in Salmonella

QSAR, Docking, and Molecular Dynamics Simulation Studies of Sigmacidins as Antimicrobials against Streptococci

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