240 research outputs found
Sortase A: An ideal target for anti-virulence drug development
No full textSortase A is a membrane enzyme responsible for the anchoring of surface-exposed proteins to the cell
wall envelope of Gram-positive bacteria. As a well-studied member of the sortase subfamily catalysing
the cell wall anchoring of important virulence factors to the surface of staphylococci, enterococci and
streptococci, sortase A plays a critical role in Gram-positive bacterial pathogenesis. It is thus considered a
promising target for the development of new anti-infective drugs that aim to interfere with important
Gram-positive virulence mechanisms, such as adhesion to host tissues, evasion of host defences, and
bio
fi
lm formation. The additional properties of sortase A as an enzyme that is not required for Gram-
positive bacterial growth or viability and is conveniently located on the cell membrane making it
more accessible to inhibitor targeting, constitute additional reasons reinforcing the view that sortase A is
an ideal target for anti-virulence drug development. Many inhibitors of sortase A have been identi
fi
ed to
date using high-throughput or
in silico
screening of compound libraries (synthetic or natural), and while
many have proved useful tools for probing the action model of the enzyme, several are also promising
candidates for the development into potent inhibitors. This review is focused on the most promising
sortase A inhibitor compounds that are currently in development as leads towards a new class of anti-
infective drugs that are urgently needed to help combat the alarming increase in antimicrobial
resistance
Biofilm capability of staphylococcus strains isolated from food and the anti-biofilm activity of a chemically synthesized pyrrolomycin
No full textThis electronic document is a “live” template. The various components of your paper [title, text, tables, figures and references] are already defined on the style sheet, as illustrated by the portions given in this document
Anti-adhesion agents against Gram-positive pathogens
No full textThe rise of antibiotic-resistance as well as the deficiency of investments by pharmaceutical companies in the development of new antibiotics, have stimulated the investigation of alternative strategies to conventional antibiotics for counteracting the pathogens. A fundamental step of Gram positive pathogenesis is the bacterial adhesion to the host tissue involving a direct and a specific interaction between bacterial surface molecules and host ligands. Targeting the adhesion is a good strategy to design novel anti-infective drugs agents useful to interfere with the pathogenic process and with a virulence mechanism as biofilm formation. This review is focused on anti-virulence compounds which target bacterial surface molecules such as exposed proteins and theicoic acids and on their potential development as therapeutic agents alternative or complementary to conventional antibiotics in the contrast of Gram positive pathogens.The rise of antibiotic-resistance as well as the deficiency of investments by pharmaceutical companies in the development of new antibiotics, have stimulated the investigation of alternative strategies to conventional antibiotics for counteracting the pathogens. A fundamental step of Gram positive pathogenesis is the bacterial adhesion to the host tissue involving a direct and a specific interaction between bacterial surface molecules and host ligands. Targeting the adhesion is a good strategy to design novel anti-infective drugs agents useful to interfere with the pathogenic process and with a virulence mechanism as biofilm formation. This review is focused on anti-virulence compounds which target bacterial surface molecules such as exposed proteins and theicoic acids and on their potential development as therapeutic agents alternative or complementary to conventional antibiotics in the contrast of Gram positive pathogens
Thiazole Analogues of the Marine Alkaloid Nortopsentin as Inhibitors of Bacterial Biofilm Formation
No full textAnti-virulence strategy is currently considered a promising approach to overcome the
global threat of the antibiotic resistance. Among different bacterial virulence factors, the biofilm
formation is recognized as one of the most relevant. Considering the high and growing percentage
of multi-drug resistant infections that are biofilm-mediated, new therapeutic agents capable of
counteracting the formation of biofilms are urgently required. In this scenario, a new series of
18 thiazole derivatives was efficiently synthesized and evaluated for its ability to inhibit biofilm
formation against the Gram-positive bacterial reference strains Staphylococcus aureus ATCC 25923
and S. aureus ATCC 6538 and the Gram-negative strain Pseudomonas aeruginosa ATCC 15442. Most of
the new compounds showed a marked selectivity against the Gram-positive strains. Remarkably,
five compounds exhibited BIC50 values against S. aureus ATCC 25923 ranging from 1.0 to 9.1 M.
The new compounds, affecting the biofilm formation without any interference on microbial growth,
can be considered promising lead compounds for the development of a new class of anti-virulence
agents
Synthesis and antimicrobial activity of new bromine-rich pyrrole derivatives related to monodeoxypyoluteorin
No full textThe synthesis and antimicrobial activity of new pyrrole derivatives structurally related to monodeoxypyoluteorin are described. The insertion of a keto or methylene spacer between the phenol group and the pyrroloyl moiety of brominated 2-(2′-hydroxybenzoyl)pyrroles leads to a decrease of the antibacterial activity
Synthesis and antitumor activities of 1,2,3-triazines and their benzo- and heterofused derivatives
No full text1,2,3-Triazines are a class of biologically active compounds that exhibit a broad spectrum of activities, including antibacterial, antifungal, antiviral, antiproliferative, analgesic and anti-inflammatory properties. This review, which covers the literature from the end of last century to 2016, treats, through a comprehensive, systematic approach, the 1,2,3-triazine and related benzo- and hetero-fused derivatives possessing antitumor activity. Their efficacy, combined with a simple synthesis confers to these molecules a great potential as scaffold for the development of antitumor compounds
A Synthetic Derivative of Antimicrobial Peptide Holothuroidin 2 from Mediterranean Sea Cucumber (Holothuria tubulosa) in the Control of Listeria monocytogenes
No full textDue to the limited number of available antibiotics, antimicrobial peptides (AMPs) are considered antimicrobial candidates to fight difficult-to-treat infections such as those associated with biofilms. Marine environments are precious sources of AMPs, as shown by the recent discovery of antibiofilm properties of Holothuroidin 2 (H2), an AMP produced by the Mediterranean sea cucumber Holothuria tubulosa. In this study, we considered the properties of a new H2 derivative, named H2d, and we tested it against seven strains of the dangerous foodborne pathogen Listeria monocytogenes. This peptide was more active than H2 in inhibiting the growth of planktonic L. monocytogenes and was able to interfere with biofilm formation at sub-minimum inhibitory concentrations (MICs). Atomic-level molecular dynamics (MD) simulations revealed insights related to the enhanced inhibitory activity of H2d, showing that the peptide is characterized by a more defined tertiary structure with respect to its ancestor. This allows the peptide to better exhibit an amphipathic character, which is an essential requirement for the interaction with cell membranes, similarly to other AMPs. Altogether, these results support the potential use of our synthetic peptide, H2d, as a template for the development of novel AMP-based drugs able to fight foodborne that are resistant to conventional antibiotics
Synthesis and biological evaluation of some new 2-phenylpropiolamidobenzamides as potential antagonists of the HMDM2-p53 protein-protein interactions
No full textAn overview of recent molecular dynamics applications as medicinal chemistry tools for the undruggable site challenge
No full textMolecular Dynamics (MD) has become increasingly popular due to the development of hardware and software solutions
and improvement in algorithms, that allowed researchers to scale up calculations in order to speed up them. MD
simulations are usually used to address protein folding issues or protein-ligand complex stability through energy profile
analysis over time. In recent years, the development of new tools able to deeply explore Potential Energy Surface (PES)
allowed researchers to focus on the dynamic nature of binding recognition process and binding-induced protein
conformational change. Moreover, modern approaches have demonstrated to be effective and reliable in calculating some
kinetic and thermodynamic parameters behind the host-guest recognition process. Starting from all of these
considerations, several efforts have been made in order to integrate MD within the virtual screening process in drug
discovery. Knowledge retrieved from MD can be, in fact, exploited as a starting point to build pharmacophores or docking
constraints in the early stage of the screening campaign as well as to define key features, in order to unravel hidden
binding modes and help the optimisation of the molecular structure of a lead compound. Based on these outcomes,
researchers are nowadays using MD as an invaluable tool to discover and target previously considered undruggable
binding sites, including protein-protein interactions and allosteric sites on protein surface. As a matter of fact, the use of
MD has been recognised as vital in the discovery of selective protein-protein interaction modulators. The use of a dynamic
overview on how the host-guest recognition occurs and of the relative conformational modifications induced, allow
researchers to optimise small molecules and small peptides capable to tightly interact within the cleft between the two
proteins.
In this review we point to present the most recent applications of MD as integrated tool to be used in the rational design
of small molecules or small peptides able to modulate undruggable targets, such as allosteric sites and protein-protein
interactions
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