TP0586532, a non-hydroxamate LpxC inhibitor, has in vitro and in vivo antibacterial activities against Enterobacteriaceae

Fujita, Komei; Takata, Isao; Yoshida, Ippei; Okumura, Hirotoshi; Otake, Katsumasa; Takashima, Hajime; Sugiyama, Hiroyuki

doi:10.1038/s41429-021-00486-3

Cited by 7 publications

(4 citation statements)

References 24 publications

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“…TP0586532 and colistin combinations showed indifferent or additive effects, and their effect was the weakest among all the tested antibiotics. TP0586532 might have a minimal effect on the antibacterial activity of colistin because colistin produces antibacterial activity by binding to LPS ( 39 ), whereas TP0586532 reduces LPS levels ( 27 ).…”

Section: Discussionmentioning

confidence: 99%

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TP0586532, a Novel Non-Hydroxamate LpxC Inhibitor: Potentiating Effect on In Vitro Activity of Meropenem against Carbapenem-Resistant Enterobacteriaceae

et al. 2022

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Section: Discussionmentioning

confidence: 99%

“…TP0586532 ( Fig. 1 ) is a novel non-hydroxamate LpxC inhibitor that shows antibacterial activity against Gram-negative bacteria, including CRE ( 27 ). Furthermore, TP0586532 had no effect on blood pressure, heart rate, or electrocardiogram findings in a cardiovascular study examining anesthetized guinea pigs ( 28 ).…”

Section: Introductionmentioning

confidence: 99%

TP0586532, a Novel Non-Hydroxamate LpxC Inhibitor: Potentiating Effect on In Vitro Activity of Meropenem against Carbapenem-Resistant Enterobacteriaceae

et al. 2022

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“…254 Recently, a non-hydroxamate molecule TP0586532 was discovered as an LpxC inhibitor with broad-spectrum activity. 255 TP0586532 showed efficacy against carbapenem-resistant bacterial pathogens in murine infection models. The absence of hydroxamate in TP0586532 makes it a good LpxC inhibitor drug with minimum toxic effects; however, it has yet to be studied further for potential clinical implications.…”

Section: Chemical Genetic Approaches To Discover Cell Wall Inhibitorsmentioning

confidence: 99%

Chemical genetic approaches for the discovery of bacterial cell wall inhibitors

Gupta,

Singh,

Pathania

2023

RSC Med. Chem.

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“…Based on the known amino acid residues required for substrate interaction and enzyme activity, many LpxC inhibitors have been developed, bioinformatically analyzed and intensively tested in vitro over the last two decades (22)(23)(24)(25)(26). Their antimicrobial activity was screened in various pathogens, e.g.…”

Section: Introductionmentioning

confidence: 99%

Same same but different – The global response ofEscherichia colito five different LpxC inhibitors

Möller,

Vázquez-Hernández,

Kutscher

et al. 2023

Preprint

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A promising but yet clinically unexploited antibiotic target in difficult-to-treat Gram-negative bacteria is LpxC, the key enzyme in the biosynthesis of lipopolysaccharides (LPS), which are the major constituents of the outer membrane. To gain insights into the mode of action of five different LpxC inhibitors, we conducted a comparative phenotypic and proteomic analysis. All five compounds bound to purified LpxC from Escherichia coli. Treatment of E. coli with these compounds changed the cell shape and stabilized LpxC suggesting that the FtsH-mediated turnover is impaired. LpxC inhibition sensitized E. coli to the cell wall antibiotic vancomycin, which typically does not cross the outer membrane. Four of the five compounds led to an accumulation of lyso-PE, a cleavage product of phosphatidylethanolamine (PE), generated by the phospholipase PldA. The combined results suggested an imbalance in phospholipid (PL) and LPS biosynthesis, which was corroborated by the global proteome response to treatment with the LpxC inhibitors. Apart from LpxC itself, FabA and FabB responsible for the biosynthesis of unsaturated fatty acids, were consistently upregulated. Our work also shows that antibiotics targeting the same enzyme do not necessarily elicit identical cellular responses. Compound-specific marker proteins belonged to different functional categories, like stress responses, nucleotide or amino acid metabolism and quorum sensing. These findings provide new insights into common and distinct cellular defense mechanisms against LpxC inhibition. Moreover, they support a delicate balance between LPS and PL biosynthesis with great potential as point of attack for antimicrobial intervention.

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TP0586532, a non-hydroxamate LpxC inhibitor, has in vitro and in vivo antibacterial activities against Enterobacteriaceae

Cited by 7 publications

References 24 publications

TP0586532, a Novel Non-Hydroxamate LpxC Inhibitor: Potentiating Effect on In Vitro Activity of Meropenem against Carbapenem-Resistant Enterobacteriaceae

TP0586532, a Novel Non-Hydroxamate LpxC Inhibitor: Potentiating Effect on In Vitro Activity of Meropenem against Carbapenem-Resistant Enterobacteriaceae

Chemical genetic approaches for the discovery of bacterial cell wall inhibitors

Same same but different – The global response ofEscherichia colito five different LpxC inhibitors

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