Small-molecule inhibitors of nisin resistance protein NSR from the human pathogen Streptococcus agalactiae

Porta, N. La; Zaschke-Kriesche, Julia; Frieg, Benedikt; Gopalswamy, Mohanraj; Živković, Aleksandra; Etzkorn, Manuel; Stark, Holger; Smits, Sander H. J.; Gohlke, Holger

doi:10.1016/j.bmc.2019.115079

Cited by 7 publications

(4 citation statements)

References 41 publications

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“…However, modified nisin molecules were able to maintain activity against strains possessing SaNSR (Hayes et al, 2019;Zaschke-Kriesche et al, 2019). Another mode of escaping the degrading activity of AMPs is via inhibitory molecules capable of binding to the nisin site of SaNSR (Porta et al, 2019). A phosphoglycerate kinase of GBS was also identified to participate in AMP resistance.…”

Section: Proteases and Other Proteinsmentioning

confidence: 99%

Resistance Mechanisms to Antimicrobial Peptides in Gram-Positive Bacteria

et al. 2020

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With the alarming increase of infections caused by pathogenic multidrug-resistant bacteria over the last decades, antimicrobial peptides (AMPs) have been investigated as a potential treatment for those infections, directly through their lytic effect or indirectly, due to their ability to modulate the immune system. There are still concerns regarding the use of such molecules in the treatment of infections, such as cell toxicity and host factors that lead to peptide inhibition. To overcome these limitations, different approaches like peptide modification to reduce toxicity and peptide combinations to improve therapeutic efficacy are being tested. Human defense peptides consist of an important part of the innate immune system, against a myriad of potential aggressors, which have in turn developed different ways to overcome the AMPs microbicidal activities. Since the antimicrobial activity of AMPs vary between Gram-positive and Gram-negative species, so do the bacterial resistance arsenal. This review discusses the mechanisms exploited by Gram-positive bacteria to circumvent killing by antimicrobial peptides. Specifically, the most clinically relevant genera, Streptococcus spp., Staphylococcus spp., Enterococcus spp. and Gram-positive bacilli, have been explored.

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Section: Proteases and Other Proteinsmentioning

confidence: 99%

Resistance Mechanisms to Antimicrobial Peptides in Gram-Positive Bacteria

et al. 2020

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“…This can lead to unsatisfactory results, especially for highly flexible ligands. Thus, threedimensional ligand screening approaches can be more effective in identifying binders that can fit into the binding site and have been used for identifying novel binders successfully in the past [15][16][17][18][19][20]. However, ligand-based screening approaches neglect explicit knowledge of the receptor structure.…”

Section: Introductionmentioning

confidence: 99%

Identification of ligands binding to MB327-PAM-1, a binding pocket relevant for resensitization of nAChRs

Kaiser,

Gertzen,

Bernauer

et al. 2023

Preprint

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Desensitization of nicotinic acetylcholine receptors (nAChRs) can be induced by overstimulation with acetylcholine (ACh) caused by an insufficient degradation of ACh after poisoning with organophosphorus compounds (OPCs). Currently, there is no generally applicable treatment for OPC poisoning that directly targets the desensitized nAChR. The bispyridinium compound MB327, an allosteric modulator of nAChR, has been shown to act as a resensitizer of nAChRs, indicating that drugs binding directly to nAChRs can have beneficial effects after OPC poisoning. However, MB327 also acts as an inhibitor of nAChRs at higher concentrations and can thus not be used for OPC poisoning treatment. Consequently, novel, more potent resensitizers are required. To successfully design novel ligands, the knowledge of the binding site is of utmost importance. Recently, we performedin silicostudies to identify a new potential binding site of MB327, MB327-PAM-1, for which a more affine ligand, UNC0646, has been described. In this work, we performed ligand-based screening approaches to identify novel analogs of UNC0646 to help further understand the structure-affinity relationship of this compound class. Furthermore, we used structure-based screenings and identified compounds representing four new chemotypes binding to MB327-PAM-1. One of these compounds, cycloguanil, is the active metabolite of the antimalaria drug proguanil and shows a higher affinity towards MB327-PAM-1 than MB327. Furthermore, cycloguanil can reestablish the muscle force in soman-inhibited rat muscles. These results can act as a starting point to develop more potent resensitizers of nAChR and to close the gap in the treatment after OPC poisoning.

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“…Nisin is an antibacterial peptide with a molecular weight of 3.3 kDa and 34 amino acids, belongs to the group A Lantibiotics, and acts against Gram-positive bacteria 24 , 25 . Nisin has many applications in food preservation and medicine, including wound healing; it acts against some species of bacteria such as Staphylococcus aureus and Clostridium difficile 26 , 27 . The mechanism of the antibacterial effect of nisin is through forming pores in the bacterial cell wall.…”

Section: Introductionmentioning

confidence: 99%

Designing a new alginate-fibrinogen biomaterial composite hydrogel for wound healing

Soleimanpour

Mirhaji

Jafari

et al. 2022

Sci Rep

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Wound healing is a complex process and rapid healing necessitates a proper micro-environment. Therefore, design and fabrication of an efficacious wound dressing is an impressive innovation in the field of wound healing. The fabricated wound dressing in this scenario was designed using a combination of the appropriate coagulating and anti-bacterial materials like fibrinogen (as coagulating agent), nisin (as anti-bacterial agent), ethylenediaminetetraacetic acid (as anti-bacterial agent), and alginate (as wound healing agent). Biophysical characterization showed that the interaction of fibrinogen and alginate was associated with minor changes in the secondary structure of the protein. Conformational studies showed that the protein was structurally stable at 42 °C, is the maximum temperature of the infected wound. The properties of the hydrogel such as swelling, mechanical resistance, nisin release, antibacterial activity, cytotoxicity, gel porosity, and blood coagulation were assessed. The results showed a slow release for the nisin during 48 h. Antibacterial studies showed an inhibitory effect on the growth of Gram-negative and Gram-positive bacteria. The hydrogel was also capable to absorb a considerable amount of water and provide oxygenation as well as incorporation of the drug into its structure due to its sufficient porosity. Scanning electron microscopy showed pore sizes of about 14–198 µm in the hydrogel. Cell viability studies indicated high biocompatibility of the hydrogel. Blood coagulation test also confirmed the effectiveness of the synthesized hydrogel in accelerating the process of blood clot formation. In vivo studies showed higher rates of wound healing, re-epithelialization, and collagen deposition. According to the findings from in vitro as well as in vivo studies, the designed hydrogel can be considered as a novel attractive wound dressing after further prerequisite assessments.

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Small-molecule inhibitors of nisin resistance protein NSR from the human pathogen Streptococcus agalactiae

Cited by 7 publications

References 41 publications

Resistance Mechanisms to Antimicrobial Peptides in Gram-Positive Bacteria

Resistance Mechanisms to Antimicrobial Peptides in Gram-Positive Bacteria

Identification of ligands binding to MB327-PAM-1, a binding pocket relevant for resensitization of nAChRs

Designing a new alginate-fibrinogen biomaterial composite hydrogel for wound healing

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