Dataset Information

Short Ligand, Cysteine-Modified Warnericin RK Antimicrobial Peptides Favor Highly Sensitive Detection of Legionella pneumophila.

ABSTRACT: Culture-based methods for the detection of Legionella pneumophila are prohibitively slow and frequently inadequate. The problem has been addressed with biosensing technology that employs a variety of ligands for the specific capture of bacteria. However, the limited success of the application of mammalian antibodies, aptamers, and nucleic acid-based probes for sensitive biosensing has generated growing interest in exploring alternative biosensing architectures, such as those based on antimicrobial peptides (AMP) that are known for their attractive therapeutic applications. We report on the successful employment of cysteine-modified warnericin RK AMP for the operation of a highly sensitive biosensor of L. pneumophila based on digital photocorrosion of GaAs/AlGaAs nanoheterostructures. The replacement of the relatively cumbersome procedure commonly applied for the attachment of antibodies to COOH-terminated mercaptohexadecanoic acid self-assembled monolayers has allowed for a significant reduction in the distance at which bacteria are immobilized above the biosensor surface. An important consequence of this approach is the attractive limit of detection of L. pneumophila estimated at 2 × 10² CFU/mL. The target bacteria were captured four times more efficiently than P. fluorescens, B. subtilis, and E. coli, which is highly promising for environmental monitoring.

SUBMITTER: Islam MA

PROVIDER: S-EPMC7818584 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Short Ligand, Cysteine-Modified Warnericin RK Antimicrobial Peptides Favor Highly Sensitive Detection of Legionella pneumophila.

Islam M Amirul MA Hassen Walid M WM Tayabali Azam F AF Dubowski Jan J JJ

ACS omega 20210106 2

Culture-based methods for the detection of Legionella pneumophila are prohibitively slow and frequently inadequate. The problem has been addressed with biosensing technology that employs a variety of ligands for the specific capture of bacteria. However, the limited success of the application of mammalian antibodies, aptamers, and nucleic acid-based probes for sensitive biosensing has generated growing interest in exploring alternative biosensing architectures, such as those based ...[more]

PMID: 33490789

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Project description:Macrophage infectivity potentiator (Mip) and Mip-like proteins are virulence factors in a wide range of pathogens including Legionella pneumophila. These proteins belong to the FK506 binding protein (FKBP) family of peptidyl-prolyl-cis/trans-isomerases (PPIases). In L. pneumophila, the PPIase activity of Mip is required for invasion of macrophages, transmigration through an in vitro lung-epithelial barrier, and full virulence in the guinea pig infection model. Additionally, Mip is a moonlighting protein that binds to collagen IV in the extracellular matrix. Here, we describe the development and synthesis of cycloheximide derivatives with adamantyl moieties as novel FKBP ligands, and analyze their effect on the viability of L. pneumophila and other bacteria. All compounds efficiently inhibited PPIase activity of the prototypic human FKBP12 as well as Mip with IC50-values as low as 180 nM and 1.7 μM, respectively. Five of these derivatives inhibited the growth of L. pneumophila at concentrations of 30-40 μM, but exhibited no effect on other tested bacterial species indicating a specific spectrum of antibacterial activity. The derivatives carrying a 3,5-dimethyladamantan-1-[yl]acetamide substitution (MT_30.32), and a 3-ethyladamantan-1-[yl]acetamide substitution (MT_30.51) had the strongest effects in PPIase- and liquid growth assays. MT_30.32 and MT_30.51 were also inhibitory in macrophage infection studies without being cytotoxic. Accordingly, by applying a combinatorial approach, we were able to generate novel, hybrid inhibitors consisting of cycloheximide and adamantane, two known FKBP inhibitors that interact with different parts of the PPIase domain, respectively. Interestingly, despite the proven Mip-inhibitory activity, the viability of a Mip-deficient strain was affected to the same degree as its wild type. Hence, we also propose that cycloheximide derivatives with adamantyl moieties are potent PPIase inhibitors with multiple targets in L. pneumophila.

Dataset Information

Short Ligand, Cysteine-Modified Warnericin RK Antimicrobial Peptides Favor Highly Sensitive Detection of Legionella pneumophila.

Publications

Short Ligand, Cysteine-Modified Warnericin RK Antimicrobial Peptides Favor Highly Sensitive Detection of <i>Legionella pneumophila</i>.

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