Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 56
Filtrar
Más filtros

Banco de datos
Tipo del documento
Intervalo de año de publicación
1.
Mol Cell ; 70(1): 83-94.e7, 2018 04 05.
Artículo en Inglés | MEDLINE | ID: mdl-29625040

RESUMEN

Growing resistance of pathogenic bacteria and shortage of antibiotic discovery platforms challenge the use of antibiotics in the clinic. This threat calls for exploration of unconventional sources of antibiotics and identification of inhibitors able to eradicate resistant bacteria. Here we describe a different class of antibiotics, odilorhabdins (ODLs), produced by the enzymes of the non-ribosomal peptide synthetase gene cluster of the nematode-symbiotic bacterium Xenorhabdus nematophila. ODLs show activity against Gram-positive and Gram-negative pathogens, including carbapenem-resistant Enterobacteriaceae, and can eradicate infections in animal models. We demonstrate that the bactericidal ODLs interfere with protein synthesis. Genetic and structural analyses reveal that ODLs bind to the small ribosomal subunit at a site not exploited by current antibiotics. ODLs induce miscoding and promote hungry codon readthrough, amino acid misincorporation, and premature stop codon bypass. We propose that ODLs' miscoding activity reflects their ability to increase the affinity of non-cognate aminoacyl-tRNAs to the ribosome.


Asunto(s)
Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Proteínas Bacterianas/biosíntesis , ADN Bacteriano/genética , Infecciones por Klebsiella/tratamiento farmacológico , Subunidades Ribosómicas Pequeñas/efectos de los fármacos , Xenorhabdus/metabolismo , Aminoaciltransferasas/genética , Aminoaciltransferasas/metabolismo , Animales , Antibacterianos/metabolismo , Bacterias/genética , Bacterias/metabolismo , Proteínas Bacterianas/genética , Sitios de Unión , Modelos Animales de Enfermedad , Femenino , Células Hep G2 , Humanos , Infecciones por Klebsiella/microbiología , Klebsiella pneumoniae/efectos de los fármacos , Klebsiella pneumoniae/genética , Klebsiella pneumoniae/metabolismo , Masculino , Ratones Endogámicos ICR , Biosíntesis de Proteínas/efectos de los fármacos , Subunidades Ribosómicas Pequeñas/genética , Subunidades Ribosómicas Pequeñas/metabolismo
2.
Arch Pharm (Weinheim) ; 356(7): e2300103, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-37199697

RESUMEN

Antibiotic resistance has increased the demand for novel treatments against multidrug-resistant microorganisms. In the research literature, 5-fluorouracil (5-FU) was proposed as an alternative due to its intrinsic antibacterial property. However, given its toxicity profile at high doses, its use in antibacterial therapy is dubious. In the quest for improving the efficacy of 5-FU, the present study intends to synthesise 5-FU derivatives and assess their susceptibility and mechanism against pathogenic bacteria. It was found that the compounds having tri-hexylphosphonium substitution on both nitrogen groups of 5-FU (6a, 6b and 6c) had considerable activity against both Gram-positive and Gram-negative bacteria. Among the active compounds, those with an asymmetric linker group 6c were found to have higher antibacterial efficacy. However, no conclusive efflux inhibition activity was found. As elucidated by electron microscopy studies, these self-assembling active phosphonium-based 5-FU derivatives caused considerable septal damage and cytosolic alterations in Staphylococcus aureus cells. In Escherichia coli, these compounds triggered plasmolysis. Interestingly, the minimal inhibitory concentration (MIC) of the most potent 5-FU derivative 6c remained constant, regardless of the bacteria's resistance profile. Further analysis revealed that compound 6c generated significant alterations in membrane permeabilization and depolarization in S. aureus and E. coli cells at the MIC. Compound 6c was found to substantially impede bacterial motility, suggesting its importance in regulating bacterial pathogenicity. Additionally, the nonhaemolytic activity of 6c suggested that it could be a potential therapeutic option for treating multidrug-resistant bacterial infections.


Asunto(s)
Antibacterianos , Antiinfecciosos , Antibacterianos/farmacología , Staphylococcus aureus , Escherichia coli , Relación Estructura-Actividad , Bacterias Gramnegativas , Bacterias Grampositivas , Antiinfecciosos/farmacología , Bacterias , Pruebas de Sensibilidad Microbiana
3.
Int J Mol Sci ; 23(20)2022 Oct 18.
Artículo en Inglés | MEDLINE | ID: mdl-36293314

RESUMEN

Gram-negative bacteria were reported as a significant cause of infections in both community and nosocomial settings. Considered as one of the greatest threats to public health, the spread of bacteria drug resistance and the lack of effective alternative treatment options remains problematic. Herein, we report a promising strategy to combat Gram-negative resistant strains consisting of the combination of a macrolide antibiotic with a polyaminoisoprenyl adjuvant derivative leading to a significant decrease of antibiotic resistance.


Asunto(s)
Antibacterianos , Bacterias Gramnegativas , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Macrólidos/farmacología , Macrólidos/uso terapéutico , Farmacorresistencia Bacteriana , Adyuvantes Farmacéuticos/farmacología , Pruebas de Sensibilidad Microbiana , Farmacorresistencia Bacteriana Múltiple
4.
Int J Mol Sci ; 23(4)2022 Feb 16.
Artículo en Inglés | MEDLINE | ID: mdl-35216303

RESUMEN

Prosthetic implants are widely used in dentistry and orthopedics and, as a result, infections can occur which cause their removal. Therefore, it is essential to propose methods of eradicating the bacteria that remain on the prosthesis during treatment. For this purpose, it is necessary to develop surfaces whose antibacterial activity can be controlled. Herein, we designed innovative and smart phosphonium self-assembled monolayer (SAM) interfaces that can be electrically activated on demand for controlling bacterial contaminations on solid surfaces. Upon electroactivation with a low potential (0.2 V for 60 min., conditions determined through a DOE), a successful stamping out of Gram-positive and Gram-negative bacterial strains was obtained with SAM-modified titanium surfaces, effectively killing 95% of Staphylococcus aureus and 90% Klebsiellapneumoniae. More importantly, no toxicity towards eukaryotic cells was observed which further enhances the biocompatible character of these novel surfaces for further implementation.


Asunto(s)
Infecciones Bacterianas , Staphylococcus aureus , Antibacterianos/farmacología , Bacterias , Bacterias Gramnegativas , Humanos , Propiedades de Superficie , Titanio/farmacología
5.
Artículo en Inglés | MEDLINE | ID: mdl-33318000

RESUMEN

Active efflux confers intrinsic resistance to multiple antibiotics in Pseudomonas aeruginosa, including old disused molecules. Beside resistance, intracellular survival is another reason for failure to eradicate bacteria with antibiotics. We evaluated the capacity of polyaminoisoprenyl potentiators (designed as efflux pump inhibitors [EPIs]) NV716 and NV731 compared to PAßN to restore the activity of disused antibiotics (doxycycline, chloramphenicol [substrates for efflux], and rifampin [nonsubstrate]) in comparison with ciprofloxacin against intracellular P. aeruginosa (strains with variable efflux levels) in THP-1 monocytes exposed over 24 h to antibiotics alone (0.003 to 100× MIC) or combined with EPIs. Pharmacodynamic parameters (apparent static concentrations [Cs] and maximal relative efficacy [Emax]) were calculated using the Hill equation of concentration-response curves. PAßN and NV731 moderately reduced (0 to 4 doubling dilutions) antibiotic MICs but did not affect their intracellular activity. NV716 markedly reduced (1 to 16 doubling dilutions) the MIC of all antibiotics (substrates or not for efflux; strains expressing efflux or not); it also improved their relative potency and maximal efficacy (i.e., lower Cs; more negative Emax) intracellularly. In parallel, NV716 reduced the persister fraction in stationary cultures when combined with ciprofloxacin. In contrast to PAßN and NV731, which act only as EPIs against extracellular bacteria, NV716 can resensitize P. aeruginosa to antibiotics whether they are substrates or not for efflux, both extracellularly and intracellularly. This suggests a complex mode of action that goes beyond a simple inhibition of efflux to reduce bacterial persistence. NV716 appears to be a useful adjuvant, including to disused antibiotics with low antipseudomonal activity, to improve their activity, including against intracellular P. aeruginosa.


Asunto(s)
Antibacterianos , Pseudomonas aeruginosa , Antibacterianos/farmacología , Cloranfenicol/farmacología , Ciprofloxacina/farmacología , Farmacorresistencia Bacteriana Múltiple , Pruebas de Sensibilidad Microbiana
6.
Proc Natl Acad Sci U S A ; 115(10): E2220-E2228, 2018 03 06.
Artículo en Inglés | MEDLINE | ID: mdl-29476011

RESUMEN

The gram-negative pathogen Providencia stuartii forms floating communities within which adjacent cells are in apparent contact, before depositing as canonical surface-attached biofilms. Because porins are the most abundant proteins in the outer membrane of gram-negative bacteria, we hypothesized that they could be involved in cell-to-cell contact and undertook a structure-function relationship study on the two porins of P. stuartii, Omp-Pst1 and Omp-Pst2. Our crystal structures reveal that these porins can self-associate through their extracellular loops, forming dimers of trimers (DOTs) that could enable cell-to-cell contact within floating communities. Support for this hypothesis was obtained by studying the porin-dependent aggregation of liposomes and model cells. The observation that facing channels are open in the two porin structures suggests that DOTs could not only promote cell-to-cell contact but also contribute to intercellular communication.


Asunto(s)
Biopelículas , Porinas/metabolismo , Providencia/fisiología , Proteínas de la Membrana Bacteriana Externa/genética , Proteínas de la Membrana Bacteriana Externa/metabolismo , Cristalografía por Rayos X , Dimerización , Porinas/química , Porinas/genética , Providencia/química , Providencia/genética
7.
Int J Mol Sci ; 22(4)2021 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-33669790

RESUMEN

In the search for an effective strategy to overcome antimicrobial resistance, a series of new morpholine-containing 5-arylideneimidazolones differing within either the amine moiety or at position five of imidazolones was explored as potential antibiotic adjuvants against Gram-positive and Gram-negative bacteria. Compounds (7-23) were tested for oxacillin adjuvant properties in the Methicillin-susceptible S. aureus (MSSA) strain ATCC 25923 and Methicillin-resistant S. aureus MRSA 19449. Compounds 14-16 were tested additionally in combination with various antibiotics. Molecular modelling was performed to assess potential mechanism of action. Microdilution and real-time efflux (RTE) assays were carried out in strains of K. aerogenes to determine the potential of compounds 7-23 to block the multidrug efflux pump AcrAB-TolC. Drug-like properties were determined experimentally. Two compounds (10, 15) containing non-condensed aromatic rings, significantly reduced oxacillin MICs in MRSA 19449, while 15 additionally enhanced the effectiveness of ampicillin. Results of molecular modelling confirmed the interaction with the allosteric site of PBP2a as a probable MDR-reversing mechanism. In RTE, the compounds inhibited AcrAB-TolC even to 90% (19). The 4-phenylbenzylidene derivative (15) demonstrated significant MDR-reversal "dual action" for ß-lactam antibiotics in MRSA and inhibited AcrAB-TolC in K. aerogenes. 15 displayed also satisfied solubility and safety towards CYP3A4 in vitro.


Asunto(s)
Antibacterianos/farmacología , Farmacorresistencia Bacteriana Múltiple/genética , Imidazoles/farmacología , Morfolinas/farmacología , Sitio Alostérico , Antibacterianos/síntesis química , Antibacterianos/química , Bacterias/efectos de los fármacos , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Interacciones Farmacológicas , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Enlace de Hidrógeno , Concentración de Iones de Hidrógeno , Imidazoles/síntesis química , Imidazoles/química , Ligandos , Pruebas de Sensibilidad Microbiana , Conformación Molecular , Simulación del Acoplamiento Molecular , Morfolinas/síntesis química , Morfolinas/química , Solubilidad , Relación Estructura-Actividad , Agua
8.
Bioorg Med Chem Lett ; 30(18): 127389, 2020 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-32717610

RESUMEN

Emergence of antibioresistance is currently a major threat of public health worldwide. Hence there is an urge need of finding new antibacterial material. Herein, we report a simple and eco-friendly method to synthesize homo and heterodicationic ionic liquids based on quaternary phosphonium and ammonium salt. In order to investigate the structure activity relationship (SAR) we measured the MICs of a series of 16 derivatives with structural variations (nature of cations and counter-ions, size of linker and alkyl side chains as well as structural symmetry) over a range of Gram-positive and Gram-negative bacterial strains from the ESKAPE group. Some of the tested structures exhibit high antimicrobial activities (MIC = 0.5 mg/L) and are active over a wide range of bacteria from Gram-positive to Gram-negative. Overall, these results reveal the strong potential of di-cationic derivatives as antibacterial agents and the determination of activities from structural features gives decisive information for future synthesis of such di-cationic structures for biocidal purpose.


Asunto(s)
Compuestos de Amonio/química , Antibacterianos/síntesis química , Líquidos Iónicos/síntesis química , Compuestos Organofosforados/química , Alcanos/química , Antibacterianos/farmacología , Cationes Bivalentes/química , Evaluación Preclínica de Medicamentos , Humanos , Líquidos Iónicos/farmacología , Pruebas de Sensibilidad Microbiana , Relación Estructura-Actividad
9.
Bioorg Med Chem Lett ; 28(5): 926-929, 2018 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-29439903

RESUMEN

We report the synthesis of new mono, di and tri phosphonium ionic liquids and the evaluation of their antibacterial activities on both Gram-positive and Gram-negative bacteria from the ESKAPE-group. Among the molecules synthesized some of them reveal a strong bactericidal activity (MIC = 0.5 mg/L) for Gram-positive bacteria (including resistant strains) comparable to that of standard antibiotics. A comparative Gram positive and Gram negative antibacterial activities shows that the nature of counter-ion has no significant effects. Interestingly, the increase of phosphonium lateral chains (from 4 to 8 carbons) results in a decrease of antibacterial activities. However, the increase of the spacer length has a positive influence on the activity on both Gram-positive and Gram-negative bacteria except for E. aerogenes. Finally, the increased charge density has no effect on the Gram-positive antibacterial activities (MIC between 2 and 4 mg/L) but seems to attenuate (except for P. aeruginosa) the discrimination between Gram-positive and Gram-negative. Overall these results suggest a unique mechanism of action of these triphenylamine-phosphonium ionic liquid derivatives.


Asunto(s)
Aminas/farmacología , Antibacterianos/farmacología , Antineoplásicos/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Líquidos Iónicos/farmacología , Compuestos Organofosforados/farmacología , Aminas/química , Antibacterianos/síntesis química , Antibacterianos/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células Hep G2 , Humanos , Líquidos Iónicos/síntesis química , Líquidos Iónicos/química , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Compuestos Organofosforados/síntesis química , Compuestos Organofosforados/química , Relación Estructura-Actividad
10.
Chembiochem ; 18(3): 276-283, 2017 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-28098416

RESUMEN

Dihydromotuporamine C and its derivatives were evaluated for their in vitro antimicrobial activities and antibiotic enhancement properties against Gram-negative bacteria and clinical isolates. The mechanism of action of one of these derivatives, MOTU-N44, was investigated against Enterobacter aerogenes by using fluorescent dyes to evaluate outer-membrane depolarization and permeabilization. Its efficiency correlated with inhibition of dye transport, thus suggesting that these molecules inhibit drug transporters by de-energization of the efflux pump rather than by direct interaction of the molecule with the pump. This suggests that depowering the efflux pump provides another strategy to address antibiotic resistance.


Asunto(s)
Alcaloides/química , Alcaloides/farmacología , Antibacterianos/farmacología , Antiinfecciosos/farmacología , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Bacterias Gramnegativas/efectos de los fármacos , Compuestos Heterocíclicos con 1 Anillo/farmacología , Poliaminas/farmacología , Antibacterianos/química , Antiinfecciosos/química , Enterobacter aerogenes/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Compuestos Heterocíclicos con 1 Anillo/química , Proteínas de Transporte de Membrana/metabolismo , Pruebas de Sensibilidad Microbiana , Poliaminas/química
11.
Curr Microbiol ; 72(5): 511-7, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-26750120

RESUMEN

The Cj1169c-encoded putative protein of Campylobacter was expressed and purified from E. coli after sequence optimization. The purified protein allowed the production of a specific rabbit antiserum that was used to study the protein expression in vitro and its subcellular localization in the bacterial cell and putative interactions with other proteins. This protein is produced in Campylobacter and it clearly localizes into the periplasmic space. The level of protein production depends on factors, including pH, temperature, osmolarity, and growth phase suggesting a role in the Campylobacter environmental adaptation. The cysteine residues present in the sequence are probably involved in disulfide bridges, which may promote covalent interactions with other proteins of the Campylobacter envelope.


Asunto(s)
Proteínas Bacterianas/aislamiento & purificación , Proteínas Bacterianas/metabolismo , Campylobacter jejuni/metabolismo , Regulación Bacteriana de la Expresión Génica , Secuencias de Aminoácidos , Animales , Proteínas Bacterianas/química , Proteínas Bacterianas/genética , Campylobacter jejuni/química , Campylobacter jejuni/genética , Clonación Molecular , Escherichia coli/genética , Escherichia coli/metabolismo , Concentración de Iones de Hidrógeno , Periplasma/química , Periplasma/genética , Periplasma/metabolismo , Transporte de Proteínas , Conejos
12.
Antibiotics (Basel) ; 13(6)2024 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-38927168

RESUMEN

The rise of multi-drug-resistant (MDR) pathogenic bacteria presents a grave challenge to global public health, with antimicrobial resistance ranking as the third leading cause of mortality worldwide. Understanding the mechanisms underlying antibiotic resistance is crucial for developing effective treatments. Efflux pumps, particularly those of the resistance-nodulation-cell division (RND) superfamily, play a significant role in expelling molecules from bacterial cells, contributing to the emergence of multi-drug resistance. These are transmembrane transporters naturally produced by Gram-negative bacteria. This review provides comprehensive insights into the modulation of RND efflux pump expression in bacterial pathogens by numerous and common molecules (bile, biocides, pharmaceuticals, additives, plant extracts, etc.). The interplay between these molecules and efflux pump regulators underscores the complexity of antibiotic resistance mechanisms. The clinical implications of efflux pump induction by non-antibiotic compounds highlight the challenges posed to public health and the urgent need for further investigation. By addressing antibiotic resistance from multiple angles, we can mitigate its impact and preserve the efficacy of antimicrobial therapies.

13.
Antibiotics (Basel) ; 13(4)2024 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-38666976

RESUMEN

The development of new and effective antimicrobial compounds is urgent due to the emergence of resistant bacteria. Natural plant flavonoids are known to be effective molecules, but their activity and selectivity have to be increased. Based on previous aurone potency, we designed new aurone derivatives bearing acetamido and amino groups at the position 5 of the A ring and managing various monosubstitutions at the B ring. A series of 31 new aurone derivatives were first evaluated for their antimicrobial activity with five derivatives being the most active (compounds 10, 12, 15, 16, and 20). The evaluation of their cytotoxicity on human cells and of their therapeutic index (TI) showed that compounds 10 and 20 had the highest TI. Finally, screening against a large panel of pathogens confirmed that compounds 10 and 20 possess large spectrum antimicrobial activity, including on bioweapon BSL3 strains, with MIC values as low as 0.78 µM. These results demonstrate that 5-acetamidoaurones are far more active and safer compared with 5-aminoaurones, and that benzyloxy and isopropyl substitutions at the B ring are the most promising strategy in the exploration of new antimicrobial aurones.

14.
Bioorg Med Chem ; 21(5): 1174-9, 2013 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-23352753

RESUMEN

Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate reagent (BOP) serves as an efficient and versatile coupling reagent for the design and synthesis of new polyamino geranic acid derivatives in moderate to good chemical yields varying from 47% to 83%. These compounds induced a significant decrease of antibiotic resistance in two Gram-negative bacterial MDR strains. Our data suggested that their mechanism of action is closely associated with the inhibition of the efflux pumps.


Asunto(s)
Antibacterianos/química , Bacterias Gramnegativas/efectos de los fármacos , Terpenos/química , Antibacterianos/síntesis química , Antibacterianos/farmacología , Farmacorresistencia Bacteriana/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Relación Estructura-Actividad , Terpenos/síntesis química , Terpenos/farmacología , Triazoles/química
15.
Biochemistry ; 51(51): 10244-9, 2012 Dec 21.
Artículo en Inglés | MEDLINE | ID: mdl-23210483

RESUMEN

The role of major porin OmpPst1 of Providencia stuartii in antibiotic susceptibility for two carbapenems is investigated by combining high-resolution conductance measurements, liposome swelling, and microbiological assays. Reconstitution of a single OmpPst1 into a planar lipid bilayer and measuring the ion current, in the presence of imipenem, revealed a concentration-dependent decrease in conductance, whereas meropenem produced well-resolved short ion current blockages. Liposome swelling assays suggested a small flux of imipenem in contrast to a rapid permeation of meropenem. The lower antibiotic susceptibility of P. stuartii to imipenem compared to meropenem correlated well with the decreased level of permeation of the former through the OmpPst1 channel.


Asunto(s)
Imipenem/metabolismo , Porinas/metabolismo , Providencia/efectos de los fármacos , Tienamicinas/metabolismo , Proteínas de la Membrana Bacteriana Externa/metabolismo , Membrana Celular/metabolismo , Farmacorresistencia Bacteriana/fisiología , Conductividad Eléctrica , Membrana Dobles de Lípidos/metabolismo , Liposomas/metabolismo , Meropenem , Pruebas de Sensibilidad Microbiana , Providencia/metabolismo
16.
Eur J Med Chem ; 238: 114496, 2022 Aug 05.
Artículo en Inglés | MEDLINE | ID: mdl-35691172

RESUMEN

Potentiators can improve antibiotic activity against difficult-to-treat Gram-negative bacteria like Escherichia coli, Klebsiella pneumoniae or Acinetobacter baumannii. They represent an appealing strategy in view of the paucity of therapeutic alternatives in case of multidrug resistance. Here, we examine the ability of the polyamino-isoprenyl compound NV716 to restore the activity of a series of disused antibiotics (rifampicin, azithromycin, linezolid, fusidic acid, novobiocin, chloramphenicol, and doxycycline, plus ciprofloxacin as an active drug) against these three species in planktonic cultures, but also in infected human monocytes and biofilms and we study its underlying mechanism of action. NV716 considerably reduced the MICs of these antibiotics (2-11 doubling dilutions), the highest synergy being observed with the more lipophilic drugs. This potentiation was related to a strong interaction of NV716 with LPS, ensuing permeabilization of the outer membrane, and leading to an increased accumulation of the antibiotics inside bacteria. Moreover, NV716 increased the relative potency of all drugs against intracellular infection by the same bacteria as well as their maximal efficacy, probably related to an improvement of antibiotic activity against persisters. Lastly, NV716 also enhanced rifampicin activity against biofilms from these three species. All these effects were observed at sub-MIC concentrations of NV716 (and thus unrelated to a bactericidal effect), and in conditions for which no toxicity was evidenced towards eukaryotic cells. Altogether, these data highlight for the first time the potential interest of NV716 as an adjuvant against these Gram-negative pathogens placed in the priority list of WHO for search of new therapies.


Asunto(s)
Antibacterianos , Rifampin , Antibacterianos/farmacología , Biopelículas , Escherichia coli , Bacterias Gramnegativas , Humanos , Pruebas de Sensibilidad Microbiana , Monocitos , Rifampin/farmacología
17.
Commun Biol ; 5(1): 871, 2022 08 25.
Artículo en Inglés | MEDLINE | ID: mdl-36008485

RESUMEN

Pseudomonas aeruginosa is intrinsically resistant to many antibiotics due to the impermeability of its outer membrane and to the constitutive expression of efflux pumps. Here, we show that the polyaminoisoprenyl compound NV716 at sub-MIC concentrations re-sensitizes P. aeruginosa to abandoned antibiotics by binding to the lipopolysaccharides (LPS) of the outer membrane, permeabilizing this membrane and increasing antibiotic accumulation inside the bacteria. It also prevents selection of resistance to antibiotics and increases their activity against biofilms. No stable resistance could be selected to NV716-itself after serial passages with subinhibitory concentrations, but the transcriptome of the resulting daughter cells shows an upregulation of genes involved in the synthesis of lipid A and LPS, and a downregulation of quorum sensing-related genes. Accordingly, NV716 also reduces motility, virulence factors production, and biofilm formation. NV716 shows a unique and highly promising profile of activity when used alone or in combination with antibiotics against P. aeruginosa, combining in a single molecule anti-virulence and potentiator effects. Additional work is required to more thoroughly understand the various functions of NV716.


Asunto(s)
Antibacterianos , Pseudomonas aeruginosa , Antibacterianos/farmacología , Biopelículas , Lipopolisacáridos/farmacología , Percepción de Quorum/genética
18.
Sci Rep ; 11(1): 4280, 2021 02 19.
Artículo en Inglés | MEDLINE | ID: mdl-33608597

RESUMEN

Producing industrially significant compounds with more environmentally friendly represents a challenging task. The large-scale production of an exogenous molecule in a host microfactory can quickly cause toxic effects, forcing the cell to inhibit production to survive. The key point to counter these toxic effects is to promote a gain of tolerance in the host, for instance, by inducing a constant flux of the neo-synthetized compound out of the producing cells. Efflux pumps are membrane proteins that constitute the most powerful mechanism to release molecules out of cells. We propose here a new biological model, Deinococcus geothermalis, organism known for its ability to survive hostile environment; with the aim of coupling the promising industrial potential of this species with that of heterologous efflux pumps to promote engineering tolerance. In this study, clones of D. geothermalis containing various genes encoding chromosomal heterologous efflux pumps were generated. Resistant recombinants were selected using antibiotic susceptibility tests to screen promising candidates. We then developed a method to determine the efflux efficiency of the best candidate, which contains the gene encoding the MdfA of Salmonella enterica serovar Choleraesuis. We observe 1.6 times more compound in the external medium of the hit recombinant than that of the WT at early incubation time. The data presented here will contribute to better understanding of the parameters required for efficient production in D. geothermalis.


Asunto(s)
Biotecnología , Deinococcus/genética , Deinococcus/metabolismo , Tolerancia a Medicamentos , Ingeniería Genética , Proteínas de Transporte de Membrana/genética , Antibacterianos/farmacología , Clonación Molecular , Deinococcus/efectos de los fármacos , Tolerancia a Medicamentos/genética , Fermentación , Expresión Génica , Genoma Bacteriano , Genómica/métodos , Proteínas de Transporte de Membrana/metabolismo
19.
Antimicrob Agents Chemother ; 54(5): 1749-52, 2010 May.
Artículo en Inglés | MEDLINE | ID: mdl-20160051

RESUMEN

The activities of two naturally occurring compounds, isobavachalcone and diospyrone, against documented strains and multidrug-resistant (MDR) Gram-negative bacterial isolates were evaluated. The results indicated that the two compounds exhibited intrinsic antibacterial activity against several Gram-negative bacteria, and their activities were significantly improved in the presence of an efflux pump inhibitor (MIC values decreased to below 10 microg/ml). In addition, the activities of isobavachalcone and diospyrone against various strains exhibiting deletions of the major efflux pump components (AcrAB, TolC) were significantly increased. The overall results indicate that isobavachalcone and diospyrone could be candidates for the development of new drugs against MDR strains and that their use in combination with efflux pump inhibitors reinforces their activity.


Asunto(s)
Chalconas/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Gramnegativas/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Proteínas de Plantas/farmacología , Proteínas Bacterianas/metabolismo , Proteínas Portadoras/metabolismo , Chalconas/química , Diospyros , Descubrimiento de Drogas , Farmacorresistencia Bacteriana , Resistencia a Múltiples Medicamentos , Enterobacter aerogenes/efectos de los fármacos , Enterobacter aerogenes/metabolismo , Enterobacter cloacae/efectos de los fármacos , Enterobacter cloacae/metabolismo , Escherichia coli/efectos de los fármacos , Escherichia coli/metabolismo , Klebsiella pneumoniae/efectos de los fármacos , Klebsiella pneumoniae/metabolismo , Proteínas de Plantas/química , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/metabolismo
20.
J Med Chem ; 63(18): 10496-10508, 2020 09 24.
Artículo en Inglés | MEDLINE | ID: mdl-32840108

RESUMEN

A series consisting of new polyaminoisoprenyl derivatives were prepared in moderate to good chemical yields varying from 32 to 64% according to two synthetic pathways: (1) using a titanium-reductive amination reaction affording a 50/50 mixture of cis and trans isomers and (2) a direct nucleophilic substitution leading to a stereoselective synthesis of the compounds of interest. These compounds were then successfully evaluated for their in vitro antibiotic enhancer properties against resistant Gram-negative bacteria of four antibiotics belonging to four different families. The mechanism of action against Enterobacter aerogenes of one of the most efficient of these chemosensitizing agents was precisely evaluated by using fluorescent dyes to measure outer-membrane permeability and to determine membrane depolarization. The weak cytotoxicity encountered led us to perform an in vivo experiment dealing with the treatment of mice infected with Salmonella typhimurium and affording preliminary promising results in terms of tolerance and efficiency of the polyaminoisoprenyl derivative 5r/doxycycline combination.


Asunto(s)
Antibacterianos/uso terapéutico , Enterobacter/efectos de los fármacos , Poliaminas/uso terapéutico , Salmonelosis Animal/tratamiento farmacológico , Salmonella/efectos de los fármacos , Terpenos/uso terapéutico , Animales , Antibacterianos/síntesis química , Antibacterianos/toxicidad , Membrana Celular/efectos de los fármacos , Permeabilidad de la Membrana Celular/efectos de los fármacos , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Ratones , Pruebas de Sensibilidad Microbiana , Poliaminas/síntesis química , Poliaminas/toxicidad , Terpenos/síntesis química , Terpenos/toxicidad
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA