Inhibitors of Sortases of Gram-Positive Bacteria and their Role in the Treatment of Infectious Diseases (Review)

Kudryavtsev, Konstantin V.; Федотчева, Т. А.; Shimanovsky, N. L.

doi:10.1007/s11094-021-02488-9

Cited by 10 publications

(11 citation statements)

References 46 publications

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“…In Bacillus (many of which are plant growth‐promoting bacteria and in some cases opportunistic pathogens), sortases are vital for plant colonization and are involved in pili and endospore biosynthesis (Budzik et al, 2007 ). Inhibition of sortases as a therapeutic target in multidrug resistant pathogens has been a hot topic (Cascioferro et al, 2014 ; Cossart & Jonquières, 2000 ; Kudryavtsev et al, 2021 ; Ouyang et al, 2018 ; Si et al, 2016 ), and could prove useful in dealing with phytopathogenic bacteria, but more research is needed to fully understand all the implications that sortases and their substrates have for plant disease. Interestingly, expansin EXLX1 from Bacillus subtilis is required for colonizing maize roots (Kerff et al, 2008 ), and although it binds insoluble peptidoglycan with high affinity in vitro, its sequence contains a sortase motif followed by a hydrophobic region (de Sandozequi et al, 2022 ), strongly suggesting it to be a substrate for a sortase.…”

Section: Surface‐exposed Proteins Anchored To the Peptidoglycan Layermentioning

confidence: 99%

Bacterial surface‐exposed lipoproteins and sortase‐mediated anchored cell surface proteins in plant infection

de Sandozequi,

Martínez‐Anaya

2023

MicrobiologyOpen

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The bacterial cell envelope is involved in all stages of infection and the study of its components and structures is important to understand how bacteria interact with the extracellular milieu. Thanks to new techniques that focus on identifying bacterial surface proteins, we now better understand the specific components involved in host–pathogen interactions. In the fight against the deleterious effects of pathogenic bacteria, bacterial surface proteins (at the cell envelope) are important targets as they play crucial roles in the colonization and infection of host tissues. These surface proteins serve functions such as protection, secretion, biofilm formation, nutrient intake, metabolism, and virulence. Bacteria use different mechanisms to associate proteins to the cell surface via posttranslational modification, such as the addition of a lipid moiety to create lipoproteins and attachment to the peptidoglycan layer by sortases. In this review, we focus on these types of proteins (and provide examples of others) that are associated with the bacterial cell envelope by posttranslational modifications and their roles in plant infection.

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Section: Surface‐exposed Proteins Anchored To the Peptidoglycan Layermentioning

confidence: 99%

Bacterial surface‐exposed lipoproteins and sortase‐mediated anchored cell surface proteins in plant infection

de Sandozequi,

Martínez‐Anaya

2023

MicrobiologyOpen

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“…Bacteria can survive in two forms: planktonic cells and biofilm, and the formation of biofilm depends on many factors, including the attachment of cell wall components to the cell wall [39]. Staphylococcal sortase A (EC 3.4.22.70) is the cysteine transpeptidase and mainly acts as an anchor surface protein [40]. About 25 years have passed since the beginning of the study of sortase A inhibitors [41], and during this time, a large amount of experimental data has accumulated [42].…”

Section: Biological Activity Of Cyclopiane Diterpenesmentioning

confidence: 99%

New Cyclopiane Diterpenes and Polyketide Derivatives from Marine Sediment-Derived Fungus Penicillium antarcticum KMM 4670 and Their Biological Activities

Yurchenko,

Zhuravleva,

Khmel

et al. 2023

Marine Drugs

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Two new cyclopiane diterpenes and a new cladosporin precursor, together with four known related compounds, were isolated from the marine sediment-derived fungus Penicillium antarcticum KMM 4670, which was re-identified based on phylogenetic inference from ITS, BenA, CaM, and RPB2 gene regions. The absolute stereostructures of the isolated cyclopianes were determined using modified Mosher’s method and quantum chemical calculations of the ECD spectra. The isolation from the natural source of two biosynthetic precursors of cladosporin from a natural source has been reported for the first time. The antimicrobial activities of the isolated compounds against Staphylococcus aureus, Escherichia coli, and Candida albicans as well as the inhibition of staphylococcal sortase A activity were investigated. Moreover, the cytotoxicity of the compounds to mammalian cardiomyocytes H9c2 was studied. As a result, new cyclopiane diterpene 13-epi-conidiogenone F was found to be a sortase A inhibitor and a promising anti-staphylococcal agent.

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“…Several studies have been devoted to the development of both covalent and non-covalent small molecule inhibitors of SrtA [ 2 , 4 , 10 , 11 , 12 , 13 ]. None of those inhibitors showed activity in the low nanomolar range, being a common prerequisite for further hit-to-lead and lead optimization stages of drug discovery.…”

Section: Introductionmentioning

confidence: 99%

Theoretical Studies of Leu-Pro-Arg-Asp-Ala Pentapeptide (LPRDA) Binding to Sortase A of Staphylococcus aureus

Shulga

Kudryavtsev

2022

Molecules

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Sortase A (SrtA) of Staphylococcus aureus is a well-defined molecular target to combat the virulence of these clinically important bacteria. However up to now no efficient drugs or even clinical candidates are known, hence the search for such drugs is still relevant and necessary. SrtA is a complex target, so many straight-forward techniques for modeling using the structure-based drug design (SBDD) fail to produce the results they used to bring for other, simpler, targets. In this work we conduct theoretical studies of the binding/activity of Leu-Pro-Arg-Asp-Ala (LPRDA) polypeptide, which was recently shown to possess antivirulence activity against S. aureus. Our investigation was aimed at establishing a framework for the estimation of the key interactions and subsequent modification of LPRDA, targeted at non-peptide molecules, with better drug-like properties than the original polypeptide. Firstly, the available PDB structures are critically analyzed and the criteria to evaluate the quality of the ligand–SrtA complex geometry are proposed. Secondly, the docking protocol was investigated to establish its applicability to the LPRDA–SrtA complex prediction. Thirdly, the molecular dynamics studies were carried out to refine the geometries and estimate the stability of the complexes, predicted by docking. The main finding is that the previously reported partially chaotic movement of the β6/β7 and β7/β8 loops of SrtA (being the intrinsically disordered parts related to the SrtA binding site) is exaggerated when SrtA is complexed with LPRDA, which in turn reveals all the signs of the flexible and structurally disordered molecule. As a result, a wealth of plausible LPRDA–SrtA complex conformations are hard to distinguish using simple modeling means, such as docking. The use of more elaborate modeling approaches may help to model the system reliably but at the cost of computational efficiency.

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Inhibitors of Sortases of Gram-Positive Bacteria and their Role in the Treatment of Infectious Diseases (Review)

Cited by 10 publications

References 46 publications

Bacterial surface‐exposed lipoproteins and sortase‐mediated anchored cell surface proteins in plant infection

Bacterial surface‐exposed lipoproteins and sortase‐mediated anchored cell surface proteins in plant infection

New Cyclopiane Diterpenes and Polyketide Derivatives from Marine Sediment-Derived Fungus Penicillium antarcticum KMM 4670 and Their Biological Activities

Theoretical Studies of Leu-Pro-Arg-Asp-Ala Pentapeptide (LPRDA) Binding to Sortase A of Staphylococcus aureus

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