Novel HldE-K Inhibitors Leading to Attenuated Gram Negative Bacterial Virulence

Desroy, Nicolas; Denis, Alexis; Oliveira, Chrystelle; Atamanyuk, Dmytro; Briet, Sophia; Faivre, Fabien; LeFralliec, Géraldine; Bonvin, Yannick; Oxoby, Mayalen; Escaich, Sonia; Floquet, Stéphanie; Drocourt, Elodie; Vongsouthi, Vanida; Durant, Lionel; Moreau, F.; Verhey, Theodore B.; Lee, Ting-Wai; Junop, M.S.; Gerusz, Vincent

doi:10.1021/jm301499r

Cited by 29 publications

(41 citation statements)

References 23 publications

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“…202 Newer antibiotics New antibiotic classes for which resistance is expected to be slow or difficult to develop are welcome arrivals. 203 Agents that suppress virulence characteristics, [204][205][206] rather than kill the microbe, should also select less strongly for resistance and are attractive candidates for co-administration with current antimicrobials, [207][208][209][210][211] although none is immediately available.…”

Section: Emerging Treatmentsmentioning

confidence: 99%

Antibiotic resistance in Enterobacteriaceae: mechanisms and clinical implications

Iredell

Brown

Tagg

2016

BMJ

287

177

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Resistance of the Enterobacteriaceae to antibiotics, especially of the β lactam type, is increasingly dominated by the mobilization of continuously expressed single genes that encode efficient drug modifying enzymes. Strong and ubiquitous selection pressure has seemingly been accompanied by a shift from "natural" resistance, such as inducible chromosomal enzymes, membrane impermeability, and drug efflux, to the modern paradigm of mobile gene pools that largely determine the epidemiology of modern antibiotic resistance. In this way, antibiotic resistance is more available than ever before to organisms such as Escherichia coli and Klebsiella pneumoniae that are important causes of major sepsis. Modulation of the phenotype by host bacteria makes gene transmission less obvious and may in part explain why tracking and control of carbapenem resistance has been particularly problematic in the Enterobacteriaceae. This review discusses the underlying principles and clinical implications of the mobility and fixation of resistance genes and the exploitable opportunities and potential threats arising from apparent limitations on diversity in these mobile gene pools. It also provides some illustrative paradoxes and clinical corollaries, as well as a summary of future options.

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Section: Emerging Treatmentsmentioning

confidence: 99%

Antibiotic resistance in Enterobacteriaceae: mechanisms and clinical implications

Iredell

Brown

Tagg

2016

BMJ

287

177

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“…For this purpose, the earlier prepared 5‐ H ‐1,2,4‐triazines 1 were subjected to react with methyllithium. It should be noted that among numerous examples for the reaction between organolithium compounds and cyclic azines, there are no such cases of introduction of alkyl fragments to the 1,2,4‐triazines except the only reported example of reaction with iso ‐propyllithium …”

Section: Methodsmentioning

confidence: 99%

Direct Introduction of a Methyl Group at the C5‐Position of 1,2,4‐Triazines: Convenient Synthesis of 6‐Functionalized 5‐Aryl‐2,2′‐bipyridines

et al. 2020

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This article describes a convenient method for the synthesis of 5‐aryl‐6‐methyl‐2,2′‐bipyridines through the direct introduction of a methyl group at the C5‐position of 1,2,4‐triazine moieties. At first 1,2,4‐triazine precursors are synthesized for this purpose. The reaction proceeds through SNH/SNips° substitution and subsequent aza‐Diels‐Alder reaction. In addition, mono‐ and dibromomethyl‐substituted 2,2’‐bipyridines are also synthesized to confirm the applicability of the present method.

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“…This is because the regulator OmpR is activated both by its cognate sensor EnvZ upon high osmolarity [46] and by the non-cognate sensor ArcB when E. coli experiences anaerobic conditions [47]. ArcB forms an anaerobiosis-responsive phosphorelay with its cognate regulator ArcA [48][49][50]. Thus, OmpR-regulated genes respond to both osmolarity and oxygen availability.…”

Section: Plos Geneticsmentioning

confidence: 99%

The phosphorelay BarA/SirA activates the non-cognate regulator RcsB in Salmonella enterica

Salvail

Groisman

2020

PLoS Genet

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To survive an environmental stress, organisms must detect the stress and mount an appropriate response. One way that bacteria do so is by phosphorelay systems that respond to a stress by activating a regulator that modifies gene expression. To ensure an appropriate response, a given regulator is typically activated solely by its cognate phosphorelay protein (s). However, we now report that the regulator RcsB is activated by both cognate and noncognate phosphorelay proteins, depending on the condition experienced by the bacterium Salmonella enterica serovar Typhimurium. The RcsC and RcsD proteins form a phosphorelay that activates their cognate regulator RcsB in response to outer membrane stress and cell wall perturbations, conditions Salmonella experiences during infection. Surprisingly, the non-cognate phosphorelay protein BarA activates RcsB during logarithmic growth in Luria-Bertani medium in three ways. That is, BarA's cognate regulator SirA promotes transcription of the rcsDB operon; the SirA-dependent regulatory RNAs CsrB and CsrC further increase RcsB-activated gene transcription; and BarA activates RcsB independently of the RcsC, RcsD, and SirA proteins. Activation of a regulator by multiple sensors broadens the spectrum of environments in which a set of genes is expressed without evolving binding sites for different regulators at each of these genes.

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Novel HldE-K Inhibitors Leading to Attenuated Gram Negative Bacterial Virulence

Cited by 29 publications

References 23 publications

Antibiotic resistance in Enterobacteriaceae: mechanisms and clinical implications

Antibiotic resistance in Enterobacteriaceae: mechanisms and clinical implications

Direct Introduction of a Methyl Group at the C5‐Position of 1,2,4‐Triazines: Convenient Synthesis of 6‐Functionalized 5‐Aryl‐2,2′‐bipyridines

The phosphorelay BarA/SirA activates the non-cognate regulator RcsB in Salmonella enterica

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