QseC inhibitors as an antivirulence approach for gram-negative pathogens

Meredith M. Curtis, Regan Russell, Cristiano G. Moreira, Adeniyi M. Adebesin, Changguang Wang, Noelle S Williams, Ronald Taussig, Don Stewart, Philippe E Zimmern, Biao Lu, Ravi N. Prasad, Chen Zhu, David A. Rasko, Jason F. Huntley, J R Falck, Vanessa Sperandio

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

Invasive pathogens interface with the host and its resident microbiota through interkingdom signaling. The bacterial receptor QseC, which is a membrane-bound histidine sensor kinase, responds to the host stress hormones epinephrine and norepinephrine and the bacterial signal AI-3, integrating interkingdom signaling at the biochemical level. Importantly, the QseC signaling cascade is exploited by many bacterial pathogens to promote virulence. Here, we translated this basic science information into development of a potent small molecule inhibitor of QseC, LED 209. Extensive structure activity relationship (SAR) studies revealed that LED209 is a potent prodrug that is highly selective for QseC. Its warhead allosterically modifies lysines in QseC, impairing its function and preventing the activation of the virulence program of several Gram-negative pathogens both in vitro and during murine infection. LED209 does not interfere with pathogen growth, possibly leading to a milder evolutionary pressure toward drug resistance. LED209 has desirable pharmacokinetics and does not present toxicity in vitro and in rodents. This is a unique antivirulence approach, with a proven broad-spectrum activity against multiple Gram-negative pathogens that cause mammalian infections.

Original languageEnglish (US)
Article numbere02165-14
JournalmBio
Volume5
Issue number6
DOIs
StatePublished - Oct 17 2014

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Virulence
Information Science
Microbiota
Prodrugs
Structure-Activity Relationship
Infection
Drug Resistance
Epinephrine
Lysine
Rodentia
Norepinephrine
Pharmacokinetics
Hormones
Pressure
Membranes
Growth
LED209
In Vitro Techniques
Histidine Kinase

ASJC Scopus subject areas

  • Microbiology
  • Virology

Cite this

Curtis, M. M., Russell, R., Moreira, C. G., Adebesin, A. M., Wang, C., Williams, N. S., ... Sperandio, V. (2014). QseC inhibitors as an antivirulence approach for gram-negative pathogens. mBio, 5(6), [e02165-14]. https://doi.org/10.1128/mBio.02165-14

QseC inhibitors as an antivirulence approach for gram-negative pathogens. / Curtis, Meredith M.; Russell, Regan; Moreira, Cristiano G.; Adebesin, Adeniyi M.; Wang, Changguang; Williams, Noelle S; Taussig, Ronald; Stewart, Don; Zimmern, Philippe E; Lu, Biao; Prasad, Ravi N.; Zhu, Chen; Rasko, David A.; Huntley, Jason F.; Falck, J R; Sperandio, Vanessa.

In: mBio, Vol. 5, No. 6, e02165-14, 17.10.2014.

Research output: Contribution to journalArticle

Curtis, MM, Russell, R, Moreira, CG, Adebesin, AM, Wang, C, Williams, NS, Taussig, R, Stewart, D, Zimmern, PE, Lu, B, Prasad, RN, Zhu, C, Rasko, DA, Huntley, JF, Falck, JR & Sperandio, V 2014, 'QseC inhibitors as an antivirulence approach for gram-negative pathogens', mBio, vol. 5, no. 6, e02165-14. https://doi.org/10.1128/mBio.02165-14
Curtis MM, Russell R, Moreira CG, Adebesin AM, Wang C, Williams NS et al. QseC inhibitors as an antivirulence approach for gram-negative pathogens. mBio. 2014 Oct 17;5(6). e02165-14. https://doi.org/10.1128/mBio.02165-14
Curtis, Meredith M. ; Russell, Regan ; Moreira, Cristiano G. ; Adebesin, Adeniyi M. ; Wang, Changguang ; Williams, Noelle S ; Taussig, Ronald ; Stewart, Don ; Zimmern, Philippe E ; Lu, Biao ; Prasad, Ravi N. ; Zhu, Chen ; Rasko, David A. ; Huntley, Jason F. ; Falck, J R ; Sperandio, Vanessa. / QseC inhibitors as an antivirulence approach for gram-negative pathogens. In: mBio. 2014 ; Vol. 5, No. 6.
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