A Cell-based Screen in Actinomyces oris to Identify Sortase Inhibitors

Gosschalk, Jason E.; Chang, Chia‐Wei; Sue, Christopher K; Siegel, Sara D.; Wu, Chenggang; Kattke, Michele D.; Yi, Sung Wook; Damoiseaux, Robert; Jung, Michael E.; Ton‐That, Hung; Clubb, Robert T.

doi:10.1038/s41598-020-65256-x

Cited by 16 publications

(21 citation statements)

References 55 publications

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“…Methionine serves as the major biological methyl donor in methylation reactions, which are essential for the biosynthesis of phospholipids, proteins, DNA, and RNA (Fontecave et al, 2004). Similar to the case of subgingival bacteria (Gosschalk et al, 2020), increased virulence could also be related to S-containing transpeptidase enzymes that covalently attach proteins to peptidoglycan precursors. Bednarova et al (2012) assigned a 688 cm −1 band (symmetric P-O-P stretching) to polyphosphates contained in yeast vacuoles.…”

Section: Average Raman Spectra From Different Candida Speciesmentioning

confidence: 99%

Raman Imaging of Pathogenic Candida auris: Visualization of Structural Characteristics and Machine-Learning Identification

et al. 2021

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Invasive fungal infections caused by yeasts of the genus Candida carry high morbidity and cause systemic infections with high mortality rate in both immunocompetent and immunosuppressed patients. Resistance rates against antifungal drugs vary among Candida species, the most concerning specie being Candida auris, which exhibits resistance to all major classes of available antifungal drugs. The presently available identification methods for Candida species face a severe trade-off between testing speed and accuracy. Here, we propose and validate a machine-learning approach adapted to Raman spectroscopy as a rapid, precise, and labor-efficient method of clinical microbiology for C. auris identification and drug efficacy assessments. This paper demonstrates that the combination of Raman spectroscopy and machine learning analyses can provide an insightful and flexible mycology diagnostic tool, easily applicable on-site in the clinical environment.

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Section: Average Raman Spectra From Different Candida Speciesmentioning

confidence: 99%

Raman Imaging of Pathogenic Candida auris: Visualization of Structural Characteristics and Machine-Learning Identification

et al. 2021

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“…Gosschalk et al (2020) developed and implemented a cell-based method to identify sortase inhibitors using Actinomyces oris ( A. oris ), based on its sortase-dependent culture growth. The advantage of this method is that it provides a realistic context for the intact enzyme inhibition in the natural microbial membrane [ 24 ]. However, the differences in A. oris sortase and Sa-SrtA could provide false positive hits.…”

Section: Screening Protocols For Identification Of Sortases Inhibitorsmentioning

confidence: 99%

Targeting Bacterial Sortases in Search of Anti-virulence Therapies with Low Risk of Resistance Development

et al. 2021

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Increasingly ineffective antibiotics and rapid spread of multi- and pan-resistant bacteria represent a global health threat; hence, the need of developing new antimicrobial medicines. A first step in this direction is identifying new molecular targets, such as virulence factors. Sortase A represents a virulence factor essential for the pathogenesis of Gram-positive pathogens, some of which have a high risk for human health. We present here an exhaustive collection of sortases inhibitors grouped by relevant chemical features: vinyl sulfones, 3-aryl acrylic acids and derivatives, flavonoids, naphtoquinones, anthraquinones, indoles, pyrrolomycins, isoquinoline derivatives, aryl β-aminoethyl ketones, pyrazolethiones, pyridazinones, benzisothiazolinones, 2-phenyl-benzoxazole and 2-phenyl-benzofuran derivatives, thiadiazoles, triazolothiadiazoles, 2-(2-phenylhydrazinylidene)alkanoic acids, and 1,2,4-thiadiazolidine-3,5-dione. This review focuses on highlighting their structure–activity relationships, using the half maximal inhibitory concentration (IC50), when available, as an indicator of each compound effect on a specific sortase. The information herein is useful for acquiring knowledge on diverse natural and synthetic sortases inhibitors scaffolds and for understanding the way their structural variations impact IC50. It will hopefully be the inspiration for designing novel effective and safe sortase inhibitors in order to create new anti-infective compounds and to help overcoming the current worldwide antibiotic shortage.

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“…A . oris is dependent on the activity of its SrtA enzyme, which is conditionally dependent on glycosylation of the GspA surface protein by the activity of an LCP enzyme [ 173 ].…”

Section: Lcp Enzymes According To Bacterial Speciesmentioning

confidence: 99%

“…The actinobacterium A. oris is a colonizer of the oral cavity where it plays a specific role in the formation of supragingival plaque [172]. A. oris is dependent on the activity of its SrtA enzyme, which is conditionally dependent on glycosylation of the GspA surface protein by the activity of an LCP enzyme [173].…”

Section: Actinomyces Orismentioning

confidence: 99%

LytR-CpsA-Psr Glycopolymer Transferases: Essential Bricks in Gram-Positive Bacterial Cell Wall Assembly

Stefanović

Hager

Schäffer

2021

IJMS

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The cell walls of Gram-positive bacteria contain a variety of glycopolymers (CWGPs), a significant proportion of which are covalently linked to the peptidoglycan (PGN) scaffolding structure. Prominent CWGPs include wall teichoic acids of Staphylococcus aureus, streptococcal capsules, mycobacterial arabinogalactan, and rhamnose-containing polysaccharides of lactic acid bacteria. CWGPs serve important roles in bacterial cellular functions, morphology, and virulence. Despite evident differences in composition, structure and underlaying biosynthesis pathways, the final ligation step of CWGPs to the PGN backbone involves a conserved class of enzymes—the LytR-CpsA-Psr (LCP) transferases. Typically, the enzymes are present in multiple copies displaying partly functional redundancy and/or preference for a distinct CWGP type. LCP enzymes require a lipid-phosphate-linked glycan precursor substrate and catalyse, with a certain degree of promiscuity, CWGP transfer to PGN of different maturation stages, according to in vitro evidence. The prototype attachment mode is that to the C6-OH of N-acetylmuramic acid residues via installation of a phosphodiester bond. In some cases, attachment proceeds to N-acetylglucosamine residues of PGN—in the case of the Streptococcus agalactiae capsule, even without involvement of a phosphate bond. A novel aspect of LCP enzymes concerns a predicted role in protein glycosylation in Actinomyces oris. Available crystal structures provide further insight into the catalytic mechanism of this biologically important class of enzymes, which are gaining attention as new targets for antibacterial drug discovery to counteract the emergence of multidrug resistant bacteria.

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A Cell-based Screen in Actinomyces oris to Identify Sortase Inhibitors

Cited by 16 publications

References 55 publications

Raman Imaging of Pathogenic Candida auris: Visualization of Structural Characteristics and Machine-Learning Identification

Raman Imaging of Pathogenic Candida auris: Visualization of Structural Characteristics and Machine-Learning Identification

Targeting Bacterial Sortases in Search of Anti-virulence Therapies with Low Risk of Resistance Development

LytR-CpsA-Psr Glycopolymer Transferases: Essential Bricks in Gram-Positive Bacterial Cell Wall Assembly

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