Evolution towards Virulence in a
            <i>Burkholderia</i>
            Two-Component System

Schaefers, Matthew M.; Wang, Benjamin; Boisvert, Nicole M.; Martini, Sarah; Bonney, Sarah; Marshall, C. W.; Laub, Michael T.; Cooper, Vaughn S.; Priebe, Gregory P.

doi:10.1128/mbio.01823-21

Cited by 5 publications

(9 citation statements)

References 71 publications

(111 reference statements)

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“…This approach was based on our previous work that found mutations within the fixL gene leading to lower FixLJ pathway activity were selected for during chronic infection in people with CF (30,31) and correlated with periods of decline in lung function in people with CF. (34) These findings lead us to the hypothesis that a small molecule activating the FixLJ pathway could make Burkholderia less pathogenic, in a way coaxing the bacteria back to its soil existence where FixLJ activity is high.…”

Section: Discussionmentioning

confidence: 99%

“…The ability of BFA compounds to inhibit the uptake of and/or intracellular survival of Burkholderia into THP-1-dervived macrophages was determined using published protocols. (33,34) Human THP-1 monocytes were differentiated into macrophages by seeding 1 mL into 24well plates at 7.5x10 5 cells/mL with 200 nM phorbol 12-myristate 13-acetate (PMA). Log-phase…”

Section: Bacterial Invasion Assaysmentioning

confidence: 99%

“…Our recent work showed that otherwise isogenic BCC constructs carrying evolved (late) fixL sequence variants are more virulent than constructs carrying ancestral (early) fixL sequence variants. (34) Interestingly, bacteria carrying these evolved fixL sequence variants have lower levels of FixLJ pathway activity, demonstrating that high levels of FixLJ pathway activity are detrimental to virulence. (34) These findings led us to the hypothesis that small-molecule activators of the Burkholderia FixLJ pathway could make the bacteria less virulent.…”

Section: Introductionmentioning

confidence: 99%

“…(34) Interestingly, bacteria carrying these evolved fixL sequence variants have lower levels of FixLJ pathway activity, demonstrating that high levels of FixLJ pathway activity are detrimental to virulence. (34) These findings led us to the hypothesis that small-molecule activators of the Burkholderia FixLJ pathway could make the bacteria less virulent. In the current study, we describe a high-throughput screen that identified 11 novel activators of the Burkholderia FixLJ pathway.…”

Section: Introductionmentioning

confidence: 99%

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Small-molecule activators of a bacterial signaling pathway inhibit virulence

Mansour,

Qi,

Yan

et al. 2023

Preprint

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TheBurkholderiagenus encompasses multiple human pathogens, including potential bioterrorism agents, that are often extensively antibiotic resistant. The FixLJ pathway inBurkholderiais a two-component system that regulates virulence. Previous work showed thatfixLJmutations arising during chronic infection confer increased virulence while decreasing the activity of the FixLJ pathway. We hypothesized that small-molecule activators of the FixLJ pathway could serve as anti-virulence therapies. Here, we developed a high-throughput assay that screened over 28,000 compounds and identified 11 that could specifically active the FixLJ pathway. Eight of these compounds, denotedBurkholderiaFixActivator (BFA) 1-8, inhibited the intracellular survival ofBurkholderiain THP-1-dervived macrophages in afixLJ-dependent manner without significant toxicity. One of the compounds, BFA1, inhibited the intracellular survival in macrophages of multipleBurkholderiaspecies. Predictive modeling of the interaction of BFA1 withBurkholderiaFixL suggests that BFA1 binds to the putative ATP/ADP binding pocket in the kinase domain, indicating a potential mechanism for pathway activation. These results indicate that small-molecule FixLJ pathway activators are promising anti-virulence agents forBurkholderiaand define a new paradigm for antibacterial therapeutic discovery.

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Section: Discussionmentioning

confidence: 99%

Section: Bacterial Invasion Assaysmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Small-molecule activators of a bacterial signaling pathway inhibit virulence

Mansour,

Qi,

Yan

et al. 2023

Preprint

Self Cite

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“…FixL or analogs have been found in other microorganisms, such as Caulobacter crescentus [65], Brucella abortus [66], Chlamydomonas reinhardtii [67] and Burkholderia cepacia [68,69]. This latter bacterium is part of a class of pathogens causing concerns in cystic fibrosis patients.…”

Section: Fixl-a Short Storymentioning

confidence: 99%

Heme-Based Gas Sensors in Nature and Their Chemical and Biotechnological Applications

Gondim

Guimarães

Sousa

2022

BioChem

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Sensing is an essential feature of life, where many systems have been developed. Diatomic molecules such as O2, NO and CO exhibit an important role in life, which requires specialized sensors. Among the sensors discovered, heme-based gas sensors compose the largest group with at least eight different families. This large variety of proteins also exhibits many distinct ways of sensing diatomic molecules and promote a response for biological adaptation. Here, we briefly describe a story of two impressive systems of heme-based oxygen sensors, FixL from Rhizobium and DevS(DosS)/DosT from Mycobacterium tuberculosis. Beyond this, we also examined many applications that have emerged. These heme-based gas sensors have been manipulated to function as chemical and biochemical analytical systems to detect small molecules (O2, CO, NO, CN−), fluorophores for imaging and bioanalysis, regulation of processes in synthetic biology and preparation of biocatalysts among others. These exciting features show the robustness of this field and multiple opportunities ahead besides the advances in the fundamental understanding of their molecular functioning.

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