Amino Acid Based Antimicrobial Agents – Synthesis and Properties

Nowak, Michał; Skwarecki, Andrzej Stanisław; Milewska, Maria J.

doi:10.1002/cmdc.202100503

Cited by 24 publications

(15 citation statements)

References 239 publications

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“…The enzymes involved in the biosynthesis of peptidoglycan (murein), an important constituent of the bacterial cell wall, are common targets of different amino acid-derived compounds with antibacterial activity [ 32 ]. Aminophosphonic acids, with a phosphorus-containing group replacing the carboxyl-one (-COOH) are amongst these amino acid analogues and derivatives.…”

Section: Discussionmentioning

confidence: 99%

Antibacterial Activity of Peptide Derivatives of Phosphinothricin against Multidrug-Resistant Klebsiella pneumoniae

et al. 2023

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The fast spread of bacteria that are resistant to many classes of antibiotics (multidrug resistant) is a global threat to human and animal health with a worrisome scenario ahead. Novel therapeutical strategies are of crucial importance to combat this phenomenon. For this purpose, we investigated the antimicrobial properties of the naturally occurring tripeptide Bialaphos and a dipeptide L-leucyl-L-phosphinoithricin, the synthesis and diastereomers separation of which are herein described. We demonstrate that these compounds are effective on clinical isolates of the human pathogen Klebsiella pneumoniae, causing hospital-acquired and community-acquired infections. The tested isolates were remarkable for their resistance to more than 20 commercial antibiotics of different classes. Based on previous literature data and our experiments consisting of glutamine supplementation, we suggest that both compounds release phosphinothricin—a well-known nanomolar inhibitor of glutamine synthetase—after their penetration in the bacterial cells; and, in this way, exert their antibacterial effect by negatively affecting nitrogen assimilation in this pathogen.

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Section: Discussionmentioning

confidence: 99%

Antibacterial Activity of Peptide Derivatives of Phosphinothricin against Multidrug-Resistant Klebsiella pneumoniae

et al. 2023

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“…The molecular profile is indicative of amino acid derivatives from asparagine, which are part of the nonspecific defense system of plants, and are reported to have antimicrobial activity [45]. The antibacterial activity of this class of specialized metabolites involves a broad spectrum of bacteria including S. aureus [46].…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, the interaction of these metabolites with plasma membrane lipids is usually facilitated by their amphipathic structure and a positive charge in physiological pH, where their cationic residues electrostatically attract negatively charged molecules (e.g., anionic phospholipids, lipopolysaccharides, or teichoic acids), enabling the accumulation of these amino acid derivatives on the membrane surface [38]. As for the antibacterial mechanism of the action of amino acid derivatives, they usually participate in the bacterial cell wall, specifically on target enzymes involved in peptidoglycan (murein) biosynthesis, and promote the catalysis of key steps in oligopeptide production, the so-called MurA-F pathway [45], and, thus, cause interruption of the respiratory process and, consequently, cell death.…”

Section: Discussionmentioning

confidence: 99%

The Roots of Deguelia nitidula as a Natural Antibacterial Source against Staphylococcus aureus Strains

et al. 2022

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Deguelia nitidula (Benth.) A.M.G.Azevedo & R.A.Camargo (Fabaceae) is an herbaceous plant distributed in the Brazilian Amazon, and it is called “raiz do sol” (sun roots). On Marajó Island, quilombola communities use its prepared roots to treat skin diseases commonly caused by fungi, viruses, and bacteria. Thus, in this study, the extract, and its fractions from D. nitidula roots were used to perform in vitro cytotoxic and antibacterial assays against Staphylococcus aureus strains. Thereafter, liquid chromatography–mass spectrometry (LC–MS) was used for the metabolite annotation process. The ethanolic extract of D. nitidula roots show significant bactericidal activity against S. aureus with IC50 82 μg.mL−1 and a selectivity index (SI) of 21.35. Furthermore, the SREFr2 and SREFr3 fractions show a potent bactericidal activity, i.e., MIC of 46.8 μg.mL−1 for both, and MBC of 375 and 93.7 μg.mL−1, respectively. As showcased, SREFr3 shows safe and effective antibacterial activity mainly in respect to the excellent selectivity index (SI = 82.06). On the other hand, SREFr2 shows low selectivity (SI = 6.8), which characterizes it as not safe for therapeutic use. Otherwise, due to a limited amount of reference MS2 spectra in public libraries, up to now, it was not possible to perform a complete metabolite annotation. Despite that, our antibacterial results for SREFr3 and correlated substructures of amino acid derivatives show that the roots of D. nitidula are a natural source of specialized metabolites, which can be isolated in the future, and then used as a support for further bio-guided research, as well as natural drug development.

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“…Many of the enzyme-based assays utilize classical targets such as enzymes that are involved in the synthesis and/or recycling of cell wall compartments, especially peptidoglycan (see section “Assays for targeting cell envelope”, MurA). Other examples include the gyrase (essential for DNA replication), ribonucleotide reductase (RNR) (essential for DNA synthesis, see section “Assays for inhibitors of DNA synthesis”), bacterial ribonuclease P (required for RNA synthesis) as well as various enzymes catalysing important steps of the vitamin-, amino acid- or coenzyme-biosynthesis [ 107 , 108 , 110 , 175 ]. Finally, proteins of the ribosomal subunits as well as assembled ribosomes are exposed to the tested compounds in such assays (see section “Assays for inhibitors of transcription and translation”) [ 161 ].…”

Section: Secondary Screening: Target-based Assaysmentioning

confidence: 99%

Overview on Strategies and Assays for Antibiotic Discovery

2022

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The increase in antibiotic resistance poses a major threat to global health. Actinomycetes, the Gram-positive bacteria of the order Actinomycetales, are fertile producers of bioactive secondary metabolites, including antibiotics. Nearly two-thirds of antibiotics that are used for the treatment of bacterial infections were originally isolated from actinomycetes strains belonging to the genus Streptomyces. This emphasizes the importance of actinomycetes in antibiotic discovery. However, the identification of a new antimicrobial compound and the exploration of its mode of action are very challenging tasks. Therefore, different approaches that enable the “detection” of an antibiotic and the characterization of the mechanisms leading to the biological activity are indispensable. Beyond bioinformatics tools facilitating the identification of biosynthetic gene clusters (BGCs), whole cell-screenings—in which cells are exposed to actinomycete-derived compounds—are a common strategy applied at the very early stage in antibiotic drug development. More recently, target-based approaches have been established. In this case, the drug candidates were tested for interactions with usually validated targets. This review focuses on the bioactivity-based screening methods and provides the readers with an overview on the most relevant assays for the identification of antibiotic activity and investigation of mechanisms of action. Moreover, the article includes examples of the successful application of these methods and suggestions for improvement.

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Amino Acid Based Antimicrobial Agents – Synthesis and Properties

Cited by 24 publications

References 239 publications

Antibacterial Activity of Peptide Derivatives of Phosphinothricin against Multidrug-Resistant Klebsiella pneumoniae

Antibacterial Activity of Peptide Derivatives of Phosphinothricin against Multidrug-Resistant Klebsiella pneumoniae

The Roots of Deguelia nitidula as a Natural Antibacterial Source against Staphylococcus aureus Strains

Overview on Strategies and Assays for Antibiotic Discovery

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