Bisphosphonic acids and related compounds as inhibitors of nucleotide‐ and polyphosphate‐processing enzymes: A PPK1 and PPK2 case study

Burda-Grabowska, Małgorzata; Macegoniuk, Katarzyna; Flick, Robert; Nocek, B.; Joachimiak, A.; Yakunin, Alexander F.; Mucha, Artur; Berlicki, Łukasz

doi:10.1111/cbdd.13439

Cited by 10 publications

(6 citation statements)

References 48 publications

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“…PPK knockout strains of pathogenic bacteria have long been known to harbor defects in stress response mechanisms and virulence factor pathways ( Fraley et al, 2007 ; Gangaiah et al, 2010 ; Chuang et al, 2013 ; Batten et al, 2016 ; Dahl et al, 2017 ). This decades old proof of concept has unsurprisingly enticed researchers to develop inhibitors targeting bacterial PPKs ( Singh et al, 2016 ; Dahl et al, 2017 ; Bashatwah et al, 2018 ; Burda-Grabowska et al, 2019 ). Although several inhibitors have been identified, these molecules suffer from their inability to selectively inhibit multiple PPK isoforms.…”

Section: Discussionmentioning

confidence: 99%

Broad-Spectrum Inhibitor of Bacterial Polyphosphate Homeostasis Attenuates Virulence Factors and Helps Reveal Novel Physiology of Klebsiella pneumoniae and Acinetobacter baumannii

et al. 2021

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Acinetobacter baumannii and Klebsiella pneumoniae currently rank amongst the most antibiotic-resistant pathogens, responsible for millions of infections each year. In the wake of this crisis, anti-virulence therapeutics targeting bacterial polyphosphate (polyP) homeostasis have been lauded as an attractive alternative to traditional antibiotics. In this work, we show that the small molecule gallein, a known G-protein βγ subunit modulator, also recently proven to have dual-specificity polyphosphate kinase (PPK) inhibition in Pseudomonas aeruginosa, in turn exhibits broad-spectrum PPK inhibition in other priority pathogens. Gallein treatment successfully attenuated virulence factors of K. pneumoniae and A. baumannii including biofilm formation, surface associated motility, and offered protection against A. baumannii challenge in a Caenorhabditis elegans model of infection. This was highlighted most importantly in the critically understudied A. baumannii, where gallein treatment phenocopied a ppk1 knockout strain of a previously uncharacterized PPK1. Subsequent analysis revealed a unique instance of two functionally and phenotypically distinct PPK1 isoforms encoded by a single bacterium. Finally, gallein was administered to a defined microbial community comprising over 30 commensal species of the human gut microbiome, demonstrating the non-disruptive properties characteristic of anti-virulence treatments as microbial biodiversity was not adversely influenced. Together, these results emphasize that gallein is a promising avenue for the development of broad-spectrum anti-virulence therapeutics.

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Section: Discussionmentioning

confidence: 99%

Broad-Spectrum Inhibitor of Bacterial Polyphosphate Homeostasis Attenuates Virulence Factors and Helps Reveal Novel Physiology of Klebsiella pneumoniae and Acinetobacter baumannii

et al. 2021

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“…This screen identified the heteroaromatic compounds NSC 35676, NSC 30205, NSC 345647, and NSC 9037 as inhibitors of PPK2 at low-micromolar concentrations [ 55 ]. More recently, a series of (bis)phosphonic acid-derived PPK2 inhibitors have been developed [ 81 ]. Initially, three aryl phosphonate inhibitor molecules were co-crystallized with C. hutchinsonii PPK2, revealing the value of a (bis)phosphonate-based scaffold for PPK2 inhibition since this moiety was observed to competitively occupy the polyP channel [ 46 ].…”

Section: Therapeutic Potential: Ppk2 Inhibitorsmentioning

confidence: 99%

Polyphosphate Kinase 2 (PPK2) Enzymes: Structure, Function, and Roles in Bacterial Physiology and Virulence

Neville

Roberge

Jia

2022

IJMS

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Inorganic polyphosphate (polyP) has been implicated in an astonishing array of biological functions, ranging from phosphorus storage to molecular chaperone activity to bacterial virulence. In bacteria, polyP is synthesized by polyphosphate kinase (PPK) enzymes, which are broadly subdivided into two families: PPK1 and PPK2. While both enzyme families are capable of catalyzing polyP synthesis, PPK1s preferentially synthesize polyP from nucleoside triphosphates, and PPK2s preferentially consume polyP to phosphorylate nucleoside mono- or diphosphates. Importantly, many pathogenic bacteria such as Pseudomonas aeruginosa and Acinetobacter baumannii encode at least one of each PPK1 and PPK2, suggesting these enzymes may be attractive targets for antibacterial drugs. Although the majority of bacterial polyP studies to date have focused on PPK1s, PPK2 enzymes have also begun to emerge as important regulators of bacterial physiology and downstream virulence. In this review, we specifically examine the contributions of PPK2s to bacterial polyP homeostasis. Beginning with a survey of the structures and functions of biochemically characterized PPK2s, we summarize the roles of PPK2s in the bacterial cell, with a particular emphasis on virulence phenotypes. Furthermore, we outline recent progress on developing drugs that inhibit PPK2 enzymes and discuss this strategy as a novel means of combatting bacterial infections.

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“…Several studies have focused on finding inhibitors of PPK (25,(41)(42)(43). One of the iden- SEMs (n = 4 independent experimental replicates).…”

Section: Sp15 Pmt3 Sp15 Pmt3mentioning

confidence: 99%

The Polyphosphate Kinase of Escherichia coli Is Required for Full Production of the Genotoxin Colibactin

Tang-Fichaux

Chagneau

Bossuet-Greif

et al. 2020

mSphere

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Bisphosphonic acids and related compounds as inhibitors of nucleotide‐ and polyphosphate‐processing enzymes: A PPK1 and PPK2 case study

Cited by 10 publications

References 48 publications

Broad-Spectrum Inhibitor of Bacterial Polyphosphate Homeostasis Attenuates Virulence Factors and Helps Reveal Novel Physiology of Klebsiella pneumoniae and Acinetobacter baumannii

Broad-Spectrum Inhibitor of Bacterial Polyphosphate Homeostasis Attenuates Virulence Factors and Helps Reveal Novel Physiology of Klebsiella pneumoniae and Acinetobacter baumannii

Polyphosphate Kinase 2 (PPK2) Enzymes: Structure, Function, and Roles in Bacterial Physiology and Virulence

The Polyphosphate Kinase of Escherichia coli Is Required for Full Production of the Genotoxin Colibactin

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