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1.
Microorganisms ; 10(9)2022 Sep 09.
Article in English | MEDLINE | ID: mdl-36144412

ABSTRACT

Apple scab is an important disease conventionally controlled by chemical fungicides, which should be replaced by more environmentally friendly alternatives. One of these alternatives could be the use of lipopeptides produced by Bacillus subtilis. The objective of this work is to study the action of the three families of lipopeptides and different mixtures of them in vitro and in vivo against Venturia inaequalis. Firstly, the antifungal activity of mycosubtilin/surfactin and fengycin/surfactin mixtures was determined in vitro by measuring the median inhibitory concentration. Then, the best lipopeptide mixture ratio was produced using Design of Experiment (DoE) to optimize the composition of the culture medium. Finally, the lipopeptides mixtures efficiency against V. inaequalis was assessed in orchards as well as the evaluation of the persistence of lipopeptides on apple. In vitro tests show that the use of fengycin or mycosubtilin alone is as effective as a mixture, with the 50-50% fengycin/surfactin mixture being the most effective. Optimization of culture medium for the production of fengycin/surfactin mixture shows that the best composition is glycerol coupled with glutamic acid. Finally, lipopeptides showed in vivo antifungal efficiency against V. inaequalis regardless of the mixture used with a 70% reduction in the incidence of scab for both mixtures (fengycin/surfactin or mycosubtilin/surfactin). The reproducibility of the results over the two trial campaigns was significantly better with the mycosubtilin/surfactin mixture. The use of B. subtilis lipopeptides to control this disease is very promising.

2.
Molecules ; 24(9)2019 May 01.
Article in English | MEDLINE | ID: mdl-31052373

ABSTRACT

Antimicrobial peptides (AMPs) are considered as potential therapeutic sources of future antibiotics because of their broad-spectrum activities and alternative mechanisms of action compared to conventional antibiotics. Although AMPs present considerable advantages over conventional antibiotics, their clinical and commercial development still have some limitations, because of their potential toxicity, susceptibility to proteases, and high cost of production. To overcome these drawbacks, the use of peptides mimics is anticipated to avoid the proteolysis, while the identification of minimalist peptide sequences retaining antimicrobial activities could bring a solution for the cost issue. We describe here new polycationic ß-amino acids combining these two properties, that we used to design small dipeptides that appeared to be active against Gram-positive and Gram-negative bacteria, selective against prokaryotic versus mammalian cells, and highly stable in human plasma. Moreover, the in vivo data activity obtained in septic mice reveals that the bacterial killing effect allows the control of the infection and increases the survival rate of cecal ligature and puncture (CLP)-treated mice.


Subject(s)
Anti-Infective Agents/administration & dosage , Anti-Infective Agents/chemical synthesis , Antimicrobial Cationic Peptides/administration & dosage , Antimicrobial Cationic Peptides/chemical synthesis , Sepsis/drug therapy , Amino Acids/chemistry , Animals , Anti-Infective Agents/chemistry , Anti-Infective Agents/pharmacology , Antimicrobial Cationic Peptides/chemistry , Antimicrobial Cationic Peptides/pharmacology , Disease Models, Animal , Drug Design , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Humans , Mice , Microbial Sensitivity Tests , Molecular Mimicry , Proteolysis , Sepsis/etiology , Sepsis/microbiology
3.
Eur J Med Chem ; 95: 185-98, 2015 May 05.
Article in English | MEDLINE | ID: mdl-25817769

ABSTRACT

In response to the extensive use of antibiotics, bacteria have evolved numerous mechanisms of defense against antimicrobial agents. Among them, extrusion of the antimicrobial agents outside the bacterial cell through efflux pumps is a major cause of concern. At first limited to one or few structurally-related antibiotics, bacterial resistance have then progressed towards cross-resistance between different classes of antibiotics, leading to multidrug-resistant microorganisms. Emergence of these pathogens requires development of novel therapeutic strategies and inhibition of efflux pumps appears to be a promising strategy that could restore the potency of existing antibiotics. NorA is the most studied chromosomal efflux pump of Staphylococcus aureus; it is known to be implied in resistance of Methicillin-resistant S. aureus (MRSA) strains against a wide range of unrelated substrates, including hydrophilic fluoroquinolones. Starting from 6-benzyloxypyridine-3-boronic acid I that we previously identified as a potential inhibitor of the NorA efflux pump against the NorA-overexpressing S. aureus 1199B strain (SA1199B), we describe here the synthesis and biological evaluation of a series of 6-(aryl)alkoxypyridine-3-boronic acids. 6-(3-Phenylpropoxy)pyridine-3-boronic acid 3i and 6-(4-phenylbutoxy)pyridine-3-boronic acid 3j were found to potentiate ciprofloxacin activity by a 4-fold increase compared to the parent compound I. In addition, it has been shown that both compounds promote Ethidium Bromide (EtBr) accumulation in SA1199B, thus corroborating their potential mode of action as NorA inhibitors.


Subject(s)
Bacterial Proteins/antagonists & inhibitors , Boronic Acids/pharmacology , Multidrug Resistance-Associated Proteins/antagonists & inhibitors , Pyridines/pharmacology , Staphylococcal Infections/drug therapy , Staphylococcus aureus/drug effects , Anti-Bacterial Agents/pharmacology , Boronic Acids/chemistry , Ciprofloxacin/pharmacology , Humans , KB Cells , Pyridines/chemistry , Staphylococcal Infections/microbiology
4.
J Antimicrob Chemother ; 70(6): 1727-37, 2015.
Article in English | MEDLINE | ID: mdl-25691323

ABSTRACT

OBJECTIVES: We report the synthesis, antibacterial activity and toxicity of 24 bis-indolic derivatives obtained during the development of new ways of synthesis of marine bis-indole alkaloids from the spongotine, topsentin and hamacanthin classes. METHODS: Innovative ways of synthesis and further structural optimizations led to bis-indoles presenting either the 1-(1H-indol-3'-yl)-1,2-diaminoethane unit or the 1-(1H-indol-3-yl)ethanamine unit. MIC determination was performed for reference and clinical strains of Staphylococcus aureus and CoNS species. MBC, time-kill kinetics, solubility, hydrophobicity index, plasma protein-binding and cytotoxicity assays were performed for lead compounds. Inhibition of the S. aureus NorA efflux pump was also tested for bis-indoles with no antistaphylococcal activity. RESULTS: Lead compounds were active against both S. aureus and CoNS species, with MICs between 1 and 4 mg/L. Importantly, the same MICs were found for MRSA and vancomycin-intermediate S. aureus strains. Early concentration-dependent bactericidal activity was observed for lead derivatives. Compounds with no intrinsic antibacterial activity could inhibit the S. aureus NorA efflux pump, which is involved in resistance to fluoroquinolones. At 0.5 mg/L, the most effective compound led to an 8-fold reduction of the ciprofloxacin MIC for the SA-1199B S. aureus strain, which overexpresses NorA. However, the bis-indole compounds displayed a high hydrophobicity index and high plasma protein binding, which significantly reduced antibacterial activity. CONCLUSIONS: We have synthesized and characterized novel bis-indole derivatives as promising candidates for the development of new antistaphylococcal treatments, with preserved activity against MDR S. aureus strains.


Subject(s)
Alkaloids/chemical synthesis , Alkaloids/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Indoles/chemical synthesis , Indoles/pharmacology , Staphylococcus/drug effects , Alkaloids/chemistry , Anti-Bacterial Agents/chemistry , Humans , Imidazoles/chemistry , Imidazolines/chemistry , Indole Alkaloids/chemistry , Indoles/chemistry , Microbial Sensitivity Tests , Microbial Viability/drug effects , Molecular Structure , Pyrazines/chemistry , Time Factors
5.
ChemMedChem ; 9(7): 1534-45, 2014 Jul.
Article in English | MEDLINE | ID: mdl-24677763

ABSTRACT

The synthesis of 37 1-(1H-indol-3-yl)ethanamine derivatives, including 12 new compounds, was achieved through a series of simple and efficient chemical modifications. These indole derivatives displayed modest or no intrinsic anti-staphylococcal activity. By contrast, several of the compounds restored, in a concentration-dependent manner, the antibacterial activity of ciprofloxacin against Staphylococcus aureus strains that were resistant to fluoroquinolones due to overexpression of the NorA efflux pump. Structure-activity relationships studies revealed that the indolic aldonitrones halogenated at position 5 of the indole core were the most efficient inhibitors of the S. aureus NorA efflux pump. Among the compounds, (Z)-N-benzylidene-2-(tert-butoxycarbonylamino)-1-(5-iodo-1H-indol-3-yl)ethanamine oxide led to a fourfold decrease of the ciprofloxacin minimum inhibitory concentration against the SA-1199B strain when used at a concentration of 0.5 mg L(-1) . To the best of our knowledge, this activity is the highest reported to date for an indolic NorA inhibitor. In addition, a new antibacterial compound, tert-butyl (2-(3-hydroxyureido)-2-(1H-indol-3-yl)ethyl)carbamate, which is not toxic for human cells, was also found.


Subject(s)
Amines/chemistry , Anti-Bacterial Agents/chemistry , Bacterial Proteins/antagonists & inhibitors , Multidrug Resistance-Associated Proteins/antagonists & inhibitors , Staphylococcus aureus/metabolism , Amines/chemical synthesis , Amines/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Bacterial Proteins/metabolism , Cell Line , Cell Proliferation/drug effects , Ciprofloxacin/pharmacology , Drug Resistance, Bacterial/drug effects , Humans , Indoles/chemistry , Microbial Sensitivity Tests , Multidrug Resistance-Associated Proteins/metabolism , Staphylococcus aureus/drug effects , Structure-Activity Relationship
6.
J Med Chem ; 57(6): 2536-48, 2014 Mar 27.
Article in English | MEDLINE | ID: mdl-24499135

ABSTRACT

Overexpression of efflux pumps is an important mechanism of bacterial resistance that results in the extrusion of antimicrobial agents outside the bacterial cell. Inhibition of such pumps appears to be a promising strategy that could restore the potency of existing antibiotics. The NorA efflux pump of Staphylococcus aureus confers resistance to a wide range of unrelated substrates, such as hydrophilic fluoroquinolones, leading to a multidrug-resistance phenotype. In this work, approximately 150 heterocyclic boronic species were evaluated for their activity against susceptible and resistant strains of S. aureus. Twenty-four hit compounds, although inactive when tested alone, were found to potentiate ciprofloxacin activity by a 4-fold increase at concentrations ranging from 0.5 to 8 µg/mL against S. aureus 1199B, which overexpresses NorA. Boron-free analogues showed no biological activity, thus revealing that the boron atom is crucial for biological activity. This work describes the first reported efflux pump inhibitory activity of boronic acid derivatives.


Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Bacterial Proteins/antagonists & inhibitors , Boronic Acids/chemical synthesis , Boronic Acids/pharmacology , Multidrug Resistance-Associated Proteins/antagonists & inhibitors , Staphylococcus aureus/drug effects , Anti-Bacterial Agents/metabolism , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Survival/drug effects , Ciprofloxacin/pharmacology , Culture Media , Drug Resistance, Bacterial , Drug Screening Assays, Antitumor , Humans , Indicators and Reagents , KB Cells , Microbial Sensitivity Tests , Structure-Activity Relationship
7.
Dalton Trans ; 41(21): 6451-7, 2012 Jun 07.
Article in English | MEDLINE | ID: mdl-22240736

ABSTRACT

Two series of ten chalcones and ten aurones, where ferrocene replaces the C ring and with diverse substituents on the A ring were synthesized. The compounds were tested against two antibiotic-sensitive bacterial strains, E. coli ATCC 25922 and S. aureus ATCC 25923, and two antibiotic-resistant strains, S. aureus SA-1199B and S. epidermidis IPF896. The unsubstituted compound and those with methoxy substitution showed an inhibitory effect on all bacterial strains at minimum inhibitory concentrations ranging between 2 and 32 mg L(-1). For four of these compounds, the effect was bactericidal, as opposed to bacteriostatic. The corresponding organic aurones did not show growth inhibition, underscoring the role of the ferrocene group. The methoxy-substituted aurones and the unsubstituted aurone also showed low micromolar (IC(50)) activity against MRC-5 non-tumoral lung cells and MDA-MB-231 breast cancer cells, suggesting non-specific toxicity.


Subject(s)
Bacteria/drug effects , Benzofurans/chemistry , Benzofurans/pharmacology , Chalcone/chemistry , Chalcone/pharmacology , Ferrous Compounds/chemistry , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/toxicity , Benzofurans/chemical synthesis , Benzofurans/toxicity , Cell Line, Tumor , Chalcone/chemical synthesis , Chalcone/toxicity , Endpoint Determination , Humans , Metallocenes , Microbial Sensitivity Tests , Time Factors
8.
Colloids Surf B Biointerfaces ; 84(2): 301-9, 2011 Jun 01.
Article in English | MEDLINE | ID: mdl-21310597

ABSTRACT

Antibacterial peptides, magainin I and nisin were covalently bound to stainless steel surfaces. Several procedures of surface functionalisation processes have been investigated and optimized, each step being characterized by polarization modulation reflection absorption infrared spectroscopy (PM-RAIRS) and X-ray photoemission spectroscopy (XPS). Grafting of antibacterial peptides was successfully achieved by a 3 steps functionalisation process on a chitosan polymeric layer. The antibacterial activity of the anchored magainin and nisin was tested against a gram-positive bacteria, Listeria ivanovii, i.e., the possible survival and attachment of this bacteria, was characterized on modified stainless steel surfaces. The results revealed that the adsorbed peptides reduced the adhesion of bacteria on the functionalised stainless steel surface.


Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Biofilms/drug effects , Peptides/chemistry , Peptides/pharmacology , Stainless Steel/chemistry , Antimicrobial Cationic Peptides/chemistry , Antimicrobial Cationic Peptides/pharmacology , Bacterial Adhesion , Chitosan/chemistry , Chitosan/pharmacology , Cross-Linking Reagents/chemistry , Cross-Linking Reagents/pharmacology , Molecular Structure , Nisin/chemistry , Nisin/pharmacology , Surface Properties
10.
Appl Microbiol Biotechnol ; 89(3): 623-34, 2011 Feb.
Article in English | MEDLINE | ID: mdl-20949268

ABSTRACT

A peptide antibiotic, gramicidin A, was covalently bound to cystamine self-assembled monolayers on gold surfaces. Each step of the surface functionalization was characterized by polarization modulation infrared reflection absorption spectroscopy and X-ray photoelectron spectroscopy. The antimicrobial activity of the anchored gramicidin was tested against three Gram-positive bacteria (Listeria ivanovii, Enterococcus faecalis, and Staphylococcus aureus), the Gram-negative bacterium Escherichia coli and the yeast Candida albicans. The results revealed that the adsorbed gramicidin reduced, from 60% for E. coli to 90% for C. albicans, the number of culturable microorganisms attached to the surface. The activity was proven to be persistent overtime, up to 6 months after the first use. The bacteria attached to the functionalized surfaces were permeabilized as shown by confocal microscopy. Taken together, these results indicate a bacteriostatic mode of action of the immobilized peptide. Finally, using green fluorescent protein-expressing bacteria, it was shown that the development of a bacterial biofilm was delayed on peptide-grafted surfaces for at least 24 h.


Subject(s)
Antimicrobial Cationic Peptides/metabolism , Biofilms/drug effects , Candida albicans/drug effects , Escherichia coli/drug effects , Gold , Gram-Positive Bacteria/drug effects , Gramicidin/metabolism , Microbial Viability/drug effects , Surface Properties
11.
Biomaterials ; 30(21): 3503-12, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19345992

ABSTRACT

An antibacterial peptide, Magainin I, was covalently bound to a mixed 11-mercaptoundecanoïc acid (MUA) and 6-mercaptohexanol (C6OH) (ratio 1:3) Self-Assembled Monolayer (SAM) on gold surfaces. Each step of the surface functionalization was characterized by Polarization Modulation Reflection Absorption InfraRed Spectroscopy (PM-RAIRS) and X-ray Photoelectron Spectroscopy (XPS). The antibacterial activity of the anchored Magainin was tested against three Gram-positive bacteria (Listeria ivanovii, Enterococcus faecalis and Staphylococcus aureus), and the results revealed that the adsorbed Magainin I reduced by more than 50% the adhesion of bacteria at the surface, together with the killing of the bacteria that nonetheless adhered to the surface. No release of the peptide was observed upon contact with the bacterial suspension; the activity has proven to be persistent overtime, up to six months after the first use.


Subject(s)
Anti-Bacterial Agents/chemistry , Antimicrobial Cationic Peptides/chemistry , Fatty Acids/chemistry , Sulfhydryl Compounds/chemistry , Xenopus Proteins/chemistry , Anti-Bacterial Agents/pharmacology , Antimicrobial Cationic Peptides/pharmacology , Gold/chemistry , Gram-Positive Bacteria/drug effects , Listeria/drug effects , Materials Testing , Models, Theoretical , Spectrophotometry, Infrared , Staphylococcus aureus/drug effects , Xenopus Proteins/pharmacology
12.
Int J Food Microbiol ; 113(1): 67-74, 2007 Jan 01.
Article in English | MEDLINE | ID: mdl-16997410

ABSTRACT

Bacteriocinogenic bacteria have been proposed to protect food products from Listeria contamination as bioprotective cultures. Lactobacillus sakei 2512 was demonstrated to inhibit the growth of Listeria on sliced cooked ham by challenge test. A liquid medium simulating ham, BHI5L200, was designed in order to select bioprotective strains for meat protection. Two strains were selected, from the 201 lactic acid bacteria screened, that produced bacteriocins at pH 5.8 in BHI5L200. The first one, Leuconostoc pseudomesenteroides 2733, produced a new bacteriocin which was purified and partially characterized. The second, Lactobacillus curvatus 2711, produced sakacin X and was shown to contain sakacin T and sakacin P structural genes. Co-culture experiments in BHI5L200 demonstrated that growth of Listeria was inhibited by L. sakei 2512 as well as by L. curvatus 2711.


Subject(s)
Anti-Bacterial Agents/pharmacology , Bacteriocins/pharmacology , Food Preservation/methods , Lactobacillus/physiology , Leuconostoc/physiology , Listeria/growth & development , Meat Products/microbiology , Animals , Anti-Bacterial Agents/biosynthesis , Antibiosis , Bacteriocins/biosynthesis , Consumer Product Safety , Food Contamination/prevention & control , Food Microbiology , Humans , Lactobacillus/classification , Lactobacillus/isolation & purification , Lactobacillus/metabolism , Leuconostoc/classification , Leuconostoc/isolation & purification , Leuconostoc/metabolism , Swine
13.
J Bacteriol ; 187(6): 2218-23, 2005 Mar.
Article in English | MEDLINE | ID: mdl-15743973

ABSTRACT

By site-specific mutagenesis, the hydrophobic conserved amino acids and the C-terminal GG doublet of the leader peptide of pre-mesentericin Y105 were demonstrated to be critical for optimal secretion of mesentericin Y105, as well as for the maturation of the pre-bacteriocin by the protease portion of the ABC transporter MesD.


Subject(s)
Bacteriocins/genetics , Bacteriocins/metabolism , Leuconostoc/genetics , Leuconostoc/metabolism , Amino Acid Sequence , Amino Acid Substitution , Bacteriocins/chemistry , Cytoplasm/metabolism , Hydrophobic and Hydrophilic Interactions , Molecular Sequence Data , Mutagenesis, Site-Directed , Protein Structure, Tertiary
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