Targeting a highly conserved domain in bacterial histidine kinases to generate inhibitors with broad spectrum activity

Fihn, Conrad; Carlson, Erin E.

doi:10.1016/j.mib.2021.03.007

Cited by 24 publications

(17 citation statements)

References 66 publications

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“…One potential pitfall is that eukaryotic kinases may have biochemical or structural features that are similar to mycobacterial SKs. For instance, the ATP‐binding Bergerat fold present in SK CA domains is also found in several mammalian proteins, namely those of the GHKL (gyrase, Hsp90, histidine kinase, MutL) family (Bem et al, 2015; Fihn & Carlson, 2021). In this case, targeting the CA domain could be accompanied by the off‐target risk of host cytotoxicity.…”

Section: Discovery Of Inhibitors Of Two‐component Systemsmentioning

confidence: 99%

Two‐component sensor histidine kinases of Mycobacterium tuberculosis: Beacons for niche navigation

Stupar

Furness

Voss

et al. 2022

Molecular Microbiology

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Intracellular bacterial pathogens such as Mycobacterium tuberculosis are remarkably adept at surviving within a host, employing a variety of mechanisms to counteract host defenses and establish a protected niche. Constant surveying of the environment is key for pathogenic mycobacteria to discern their immediate location and coordinate the expression of genes necessary for adaptation. Two‐component systems efficiently perform this role, typically comprised of a transmembrane sensor kinase and a cytoplasmic response regulator. In this review, we describe the role of two‐component systems in bacterial pathogenesis, focusing predominantly on the role of sensor kinases of M. tuberculosis. We highlight important features of sensor kinases in mycobacterial infection, discuss ways in which these signaling proteins sense and respond to environments, and how this is attuned to their intracellular lifestyle. Finally, we discuss recent studies which have identified and characterized inhibitors of two‐component sensor kinases toward establishing a new strategy in anti‐mycobacterial therapy.

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Section: Discovery Of Inhibitors Of Two‐component Systemsmentioning

confidence: 99%

Two‐component sensor histidine kinases of Mycobacterium tuberculosis: Beacons for niche navigation

Stupar

Furness

Voss

et al. 2022

Molecular Microbiology

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“…In addition, histidine kinases (HK) were included as a target in the search for antibacterials [ 194 , 195 , 196 ]. HK are membrane receptors, which control a variety of cellular responses (e.g., virulence, secretion systems and antibiotic resistance).…”

Section: Secondary Screening: Target-based Assaysmentioning

confidence: 99%

Overview on Strategies and Assays for Antibiotic Discovery

2022

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The increase in antibiotic resistance poses a major threat to global health. Actinomycetes, the Gram-positive bacteria of the order Actinomycetales, are fertile producers of bioactive secondary metabolites, including antibiotics. Nearly two-thirds of antibiotics that are used for the treatment of bacterial infections were originally isolated from actinomycetes strains belonging to the genus Streptomyces. This emphasizes the importance of actinomycetes in antibiotic discovery. However, the identification of a new antimicrobial compound and the exploration of its mode of action are very challenging tasks. Therefore, different approaches that enable the “detection” of an antibiotic and the characterization of the mechanisms leading to the biological activity are indispensable. Beyond bioinformatics tools facilitating the identification of biosynthetic gene clusters (BGCs), whole cell-screenings—in which cells are exposed to actinomycete-derived compounds—are a common strategy applied at the very early stage in antibiotic drug development. More recently, target-based approaches have been established. In this case, the drug candidates were tested for interactions with usually validated targets. This review focuses on the bioactivity-based screening methods and provides the readers with an overview on the most relevant assays for the identification of antibiotic activity and investigation of mechanisms of action. Moreover, the article includes examples of the successful application of these methods and suggestions for improvement.

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“…It is, therefore, reasonable to assume that an HK inhibitor targeting multiple HKs could represent an innovative antivirulence drug against pathogenic bacteria [ 133 ]. Indeed, to identify molecules with broad anti-HK activity, Wilke et al [ 134 ] targeted the ATP-binding domain (CA) of HKs and performed high-throughput screening of 53,000 diverse small molecules, but the most potent compounds proved cytotoxic [ 134 , 135 ]. Other studies led to the identification of an HK inhibitor, waldiomycin, able to bind to the Hbox region commonly conserved in the DHp domain of HKs [ 136 ].…”

Section: Prospects: Drug Discovery Targeting Tcs Networkmentioning

confidence: 99%

Roles of Two-Component Signal Transduction Systems in Shigella Virulence

et al. 2022

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Two-component signal transduction systems (TCSs) are widespread types of protein machinery, typically consisting of a histidine kinase membrane sensor and a cytoplasmic transcriptional regulator that can sense and respond to environmental signals. TCSs are responsible for modulating genes involved in a multitude of bacterial functions, including cell division, motility, differentiation, biofilm formation, antibiotic resistance, and virulence. Pathogenic bacteria exploit the capabilities of TCSs to reprogram gene expression according to the different niches they encounter during host infection. This review focuses on the role of TCSs in regulating the virulence phenotype of Shigella, an intracellular pathogen responsible for severe human enteric syndrome. The pathogenicity of Shigella is the result of the complex action of a wide number of virulence determinants located on the chromosome and on a large virulence plasmid. In particular, we will discuss how five TCSs, EnvZ/OmpR, CpxA/CpxR, ArcB/ArcA, PhoQ/PhoP, and EvgS/EvgA, contribute to linking environmental stimuli to the expression of genes related to virulence and fitness within the host. Considering the relevance of TCSs in the expression of virulence in pathogenic bacteria, the identification of drugs that inhibit TCS function may represent a promising approach to combat bacterial infections.

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Targeting a highly conserved domain in bacterial histidine kinases to generate inhibitors with broad spectrum activity

Cited by 24 publications

References 66 publications

Two‐component sensor histidine kinases of Mycobacterium tuberculosis: Beacons for niche navigation

Two‐component sensor histidine kinases of Mycobacterium tuberculosis: Beacons for niche navigation

Overview on Strategies and Assays for Antibiotic Discovery

Roles of Two-Component Signal Transduction Systems in Shigella Virulence

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