Synthetic Low-Molecular-Mass Compounds as Potential Inhibitors of Staphylococcus Aureus Adhesion in Experiment

Божкова, С. А.; Gordina, E.M.; Labutin, Dmitry; Sokolov, Mikhail N.; Kudryatsev, K. V.

doi:10.1007/s11094-022-02570-w

Cited by 4 publications

(7 citation statements)

References 16 publications

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“…The influence of LPRDA on staphylococcal adhesive properties was evaluated using preliminary incubation of the studied bacterial strains with LPRDA for 18 h and subsequent microscopic detection of adhesion cases of the modified staphylococci to African green monkey kidney epithelial cells (Vero) [ 19 ]. The following parameters were determined from the adhesion experiments: adhesion index (AI), defined as the average number of attached bacterial cells per eukaryotic cell; percentage of infected cells (PI), defined as the proportion of Vero cells with bacteria adhered to their surface; microbial load (ML), defined as a product AI×PI; and adhesion inhibition index (AII), defined as the ratio of experimental AI to control.…”

Section: Resultsmentioning

confidence: 99%

“…We recently demonstrated that incubation of the S. aureus ATCC 29213 (MSSA) strain with small-molecule compounds from our in-house collection attenuated subsequent bacterial adhesion to Vero cells, which was in contrast to untreated staphylococci [ 19 ]. Furthermore, we predicted the properties of SrtA inhibitors for the same compounds [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

“…Recently, Wang et al discussed the oligopeptidic SrtA inhibitor LPRDA, which has been studied not only in in vitro enzyme assays but has also demonstrated protection against S. aureus -induced mastitis in a mouse model [ 18 ]. Due to our interest in the development of novel antibacterials with antiadhesive mechanisms of action [ 19 ], we selected a reference compound with confirmed activity and further potential for development. We previously demonstrated antiadhesive activity in a dual-cell assay [ 19 ] and predicted the properties of SrtA inhibitors [ 20 ] for some compounds from our in-house collection.…”

Section: Introductionmentioning

confidence: 99%

“…Due to our interest in the development of novel antibacterials with antiadhesive mechanisms of action [ 19 ], we selected a reference compound with confirmed activity and further potential for development. We previously demonstrated antiadhesive activity in a dual-cell assay [ 19 ] and predicted the properties of SrtA inhibitors [ 20 ] for some compounds from our in-house collection. After analyzing the available body of data [ 12 , 13 , 14 , 15 , 16 , 17 ], we concluded that the oligopeptide LPRDA has certain advantages over other SrtA inhibitors, primarily owing to good solubility, in vivo activity, and being a starting point for peptidomimetic development with modified properties.…”

Section: Introductionmentioning

confidence: 99%

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Oligopeptide Sortase Inhibitor Modulates Staphylococcus aureus Cell Adhesion and Biofilm Formation

et al. 2022

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Prevention of bacterial adhesion is one of the most important antivirulence strategies for meeting the global challenge posed by antimicrobial resistance. We aimed to investigate the influence of a peptidic S. aureus sortase A inhibitor on bacterial adhesion to eukaryotic cells and biofilm formation as a potential method for reducing S. aureus virulence. The pentapeptide LPRDA was synthesized and characterized as a pure individual organic compound. Incubation of MSSA and MRSA strains with LPRDA induced a subsequent reduction in staphylococcal adhesion to Vero cells and biofilm formation, as visualized by microscopic and spectrophotometric methods, respectively. LPRDA did not have a cytotoxic effect on eukaryotic or bacterial cells. The pentapeptide LPRDA deserves further investigation using in vitro and in vivo models of Gram-positive bacteriemia as a potential antibacterial agent with an antiadhesive mechanism of action.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Oligopeptide Sortase Inhibitor Modulates Staphylococcus aureus Cell Adhesion and Biofilm Formation

et al. 2022

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“…Our long-term aim is to use our expertise gained in covalent [ 16 ] and non-covalent small molecule [ 9 , 17 ] SrtA inhibitor development to start a new project using LPRDA oligopeptide as a base and, first, reveal the key interaction patterns for the LPRDA–SrtA complex, and, second, by gradual modification, come to a more potent and more drug-like lead compound [ 18 ] using SBDD methods and subsequent experimental validation. In this work we make an effort to establish protocols pertinent to computer-aided SBDD for further rational modifications and development by starting from the molecular modeling section of the work by Wang et al [ 15 ].…”

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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The Complete Assessment of Small Molecule and Peptidomimetic Inhibitors of Sortase A Towards Antivirulence Treatment

Hintzen,

Abujubara,

Tietze

et al. 2024

Chemistry A European J

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This review covers the most recent advances in the development of inhibitors for the bacterial enzyme sortase A (SrtA). Sortase A (SrtA) is a critical virulence factor present ubiquitously in Gram‐positive bacteria of which many are considered pathogenic. Sortases are key enzymes regulating bacterial adherence to host cells, by anchoring extracellular matrix‐binding proteins to the bacterial outer cell wall. By targeting virulence factors, effective treatment can be achieved, without inducing antibiotic resistance to the treatment. All in all, this would lead to a more sustainable, long‐term approach to treating bacterial infections, including ones that display multiple resistance to current therapeutics. Currently, it appears there are many promising approaches available that have the potential to advance into further clinical development, with peptidomimetic and in vivo active small molecules among the most promising. There are currently no approved drugs on the market targeting SrtA, despite its promise, adding to the relevance of this review article, as it extends to the pharmaceutical industry additionally to academic researchers.

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Synthetic Low-Molecular-Mass Compounds as Potential Inhibitors of Staphylococcus Aureus Adhesion in Experiment

Cited by 4 publications

References 16 publications

Oligopeptide Sortase Inhibitor Modulates Staphylococcus aureus Cell Adhesion and Biofilm Formation

Oligopeptide Sortase Inhibitor Modulates Staphylococcus aureus Cell Adhesion and Biofilm Formation

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

The Complete Assessment of Small Molecule and Peptidomimetic Inhibitors of Sortase A Towards Antivirulence Treatment

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