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1.
Sci Adv ; 9(23): eadg4205, 2023 06 09.
Artículo en Inglés | MEDLINE | ID: mdl-37294761

RESUMEN

In the face of the alarming rise in global antimicrobial resistance, only a handful of novel antibiotics have been developed in recent decades, necessitating innovations in therapeutic strategies to fill the void of antibiotic discovery. Here, we established a screening platform mimicking the host milieu to select antibiotic adjuvants and found three catechol-type flavonoids-7,8-dihydroxyflavone, myricetin, and luteolin-prominently potentiating the efficacy of colistin. Further mechanistic analysis demonstrated that these flavonoids are able to disrupt bacterial iron homeostasis through converting ferric iron to ferrous form. The excessive intracellular ferrous iron modulated the membrane charge of bacteria via interfering the two-component system pmrA/pmrB, thereby promoting the colistin binding and subsequent membrane damage. The potentiation of these flavonoids was further confirmed in an in vivo infection model. Collectively, the current study provided three flavonoids as colistin adjuvant to replenish our arsenals for combating bacterial infections and shed the light on the bacterial iron signaling as a promising target for antibacterial therapies.


Asunto(s)
Proteínas Bacterianas , Colistina , Colistina/farmacología , Proteínas Bacterianas/metabolismo , Antibacterianos/farmacología , Antibacterianos/metabolismo , Bacterias/metabolismo , Hierro , Homeostasis
2.
J Control Release ; 351: 896-906, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-36202152

RESUMEN

Targeted antibiotic delivery system would be an ideal solution for the treatment of enteropathogenic infections since it avoids the excessive usage of antibiotics clinically, which may lead to threat on public health and food safety. Salmonella spp. are Enteropathogens, but they are also robust H2S producers in the intestinal tracts of hosts. To this end, the PEGylated poly (α lipoic acid) (PEG-PALA) copolymer nanoparticles with hydrophilic exterior and hydrophobic interior were designated in this study to encapsulate the antibiotics and release them in response to H2S produced by Salmonella spp. The PEG-PALA nanoparticles demonstrated excellent stability in vitro and biocompatibility toward mammalian Caco-2 and 293 T cells. The release of ciprofloxacin from PEG-PALA nanoparticle was only 25.44 ± 0.57% and 26.98 ± 1.93% (w/w) in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) solutions without H2S stimulation. However, the release amounts of ciprofloxacin were up to 73.68 ± 1.63% (w/w) in the presence of 1 mM Na2S as H2S source. In the mouse infection model, PEG-PALA nanoparticles encapsulated with ciprofloxacin (PEG-PALA@CIP) reduced the Salmonella colonization in the heart, liver, spleen, lung, cecum, and faeces, prolonged ciprofloxacin persistence in the intestine while reducing its absorption into the blood. More importantly, these nanoparticles reduced 3.4-fold of Enterobacteriaceae levels and increased 1.5-fold of the Lactobacillaceae levels compared with the drug administered in the free form. Moreover, these nanoparticles resulted in only minimal signs of intestinal tract inflammation. The H2S-responsive antibiotic delivery systems reported in this study demonstrating a variety of advantages including protected the drug from deactivation by gastric and intestinal fluids, maintained a high concentration in the intestinal tract and maximally kept the gut microbiota homeostasis. As such, this targeted antibiotic delivery systems are for the encapsulation of antibiotics to target specific enteropathogens.


Asunto(s)
Nanopartículas , Ácido Tióctico , Humanos , Ratones , Animales , Ciprofloxacina/química , Células CACO-2 , Nanopartículas/química , Salmonella , Antibacterianos/química , Polietilenglicoles/química , Sistemas de Liberación de Medicamentos , Mamíferos
3.
Sci Total Environ ; 758: 143654, 2021 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-33277010

RESUMEN

Vast reservoirs of antibiotic resistance genes (ARG) are discharged into the environment via pig manure. We used metagenomic analysis to follow the distribution and shifts of ARGs and their bacterial hosts along wastewater treatment in three large pig farms. The predominating ARGs potentially encoded resistance to tetracycline (28.13%), aminoglycosides (23.64%), macrolide-lincosamide-streptogramin (MLS) (12.17%), sulfonamides (11.53%), multidrug (8.74%) and chloramphenicol (6.18%). The total relative ARG abundance increased along the treatment pathway prior to anaerobic digestion that had a similar degradative capacity for different ARGs and these ARGs were reduced by about 25% after digestion, but ARGs enriched erratically in manured soils. Distinctive ARG distribution patterns were found according to the three sample locations; feces, soil and wastewater and the differences were primarily due to the tetracycline ARGs (feces > wastewater > soil), sulfonamide ARGs (soil > wastewater > feces) and MLS ARGs (feces > wastewater > soil). Metagenomic assembly-based host analyses indicated the Proteobacteria, Firmicutes, Actinobacteria and Bacteroidetes were primary ARG carriers. The Streptococcaceae increased the abundance of multidrug, MLS and aminoglycoside ARGs in feces; Moraxellaceae were the primary contributors to the high abundance of multidrug ARGs in wastewater; the Comamonadaceae led to the higher abundance of bacA in wastewater and soil than feces. We found a high level of heterogeneity for both ARGs and ARG-hosts in the wastewater treatment system and in the agricultural soils for these pig farms.


Asunto(s)
Estiércol , Purificación del Agua , Animales , Antibacterianos , Farmacorresistencia Microbiana/genética , Granjas , Genes Bacterianos , Suelo , Microbiología del Suelo , Porcinos
4.
J Antimicrob Chemother ; 74(1): 87-95, 2019 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-30346547

RESUMEN

Objectives: The emergence of NDM- and MCR-1-co-producing Escherichia coli has compromised the use of carbapenems and colistin, which are critically important in clinical therapy, and represents a severe threat to public health worldwide. Here, we demonstrate synergism of colistin combined with existing antibiotics as a potential strategy to overcome XDR E. coli co-harbouring NDM and MCR-1 genes. Methods: To comprehensively evaluate their combined activity, antibiotic combinations were tested against 34 different E. coli strains carrying both NDM and MCR-1 genes. Antibiotic resistance profiles and molecular characteristics were investigated by susceptibility testing, PCR, MLST, S1-PFGE and WGS. Antibiotic synergistic efficacy was evaluated through in vitro chequerboard experiments and dose-response assays. A mouse model was used to confirm active combination therapies. Additionally, combinations were tested for their ability to prevent high-level colistin-resistant mutants (HLCRMs). Results: Combinations of colistin with rifampicin, rifabutin and minocycline showed synergistic activity against 34 XDR NDM- and MCR-1-co-producing E. coli strains, restoring, in part, susceptibility to both colistin and the partnering antibiotics. The therapeutic effectiveness of colistin combined with rifampicin or minocycline was demonstrated in a mouse model. Furthermore, colistin plus rifampicin showed significant activity in preventing the occurrence of HLCRMs. Conclusions: The synergism of colistin in combinations with rifampicin, rifabutin or minocycline offers viable therapeutic alternatives against XDR NDM- and MCR-positive E. coli.


Asunto(s)
Antibacterianos/administración & dosificación , Colistina/administración & dosificación , Farmacorresistencia Bacteriana , Infecciones por Escherichia coli/tratamiento farmacológico , Proteínas de Escherichia coli/metabolismo , Escherichia coli/efectos de los fármacos , beta-Lactamasas/metabolismo , Animales , Antibacterianos/farmacología , Colistina/farmacología , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Quimioterapia Combinada/métodos , Escherichia coli/enzimología , Femenino , Técnicas de Genotipaje , Ratones Endogámicos ICR , Pruebas de Sensibilidad Microbiana , Resultado del Tratamiento
5.
J Antimicrob Chemother ; 73(7): 1899-1907, 2018 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-29897466

RESUMEN

Objectives: The chloramphenicol/florfenicol resistance gene cfr, which mediates cross-resistance to linezolid and other classes of antimicrobial agents, represents a global therapeutic challenge due to its dissemination among MDR nosocomial pathogens, including MRSA. This study aimed to compare the efficacy of the linezolid/rifampicin combination in a murine pneumonia model caused by cfr-positive and cfr-negative clinical MRSA strains. Methods: Synergistic activity between linezolid and rifampicin was evaluated by chequerboard and time-kill assays. Pharmacokinetic profiles in plasma and epithelial lining fluid (ELF) as well as the therapeutic efficacy of linezolid alone and in combination with rifampicin were investigated in a murine pneumonia model. The Emax Hill equation was used to model the dose-response relationship. Results: Increased susceptibility of the study MRSA strains to linezolid was observed with the rifampicin combination (MIC decreased 2- to 16-fold versus linezolid alone). The combination had synergistic activity (fractional inhibitory concentration index ≤0.5) against all cfr-positive MRSA isolates. Linezolid demonstrated excellent pulmonary penetration with an ELF/fplasma AUC ratio of 2.68 ±âŸ0.17. The addition of rifampicin significantly improved the efficacy of linezolid in the pneumonia model due to cfr-positive and cfr-negative MRSA strains. The fAUC/MIC targets of linezolid associated with stasis, 1 log10 kill and 2 log10 kill were 15.9, 38.8 and 175 in plasma, and 43.5, 108 and 415 in ELF, respectively. Importantly, the linezolid fAUC/MIC targets in both plasma and ELF were 2.4-6.7 times lower in combined linezolid/rifampicin therapy versus linezolid monotherapy (P < 0.005). Conclusions: Combination of linezolid with rifampicin significantly improved the efficacy of linezolid in the murine pneumonia model caused by MRSA strains in the presence and absence of the cfr gene.


Asunto(s)
Antibacterianos/uso terapéutico , Linezolid/uso terapéutico , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Neumonía Bacteriana/tratamiento farmacológico , Rifampin/uso terapéutico , Infecciones Estafilocócicas/tratamiento farmacológico , Animales , Proteínas Bacterianas/genética , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Quimioterapia Combinada , Femenino , Ratones , Ratones Endogámicos ICR , Pruebas de Sensibilidad Microbiana , Organismos Libres de Patógenos Específicos
6.
Artículo en Inglés | MEDLINE | ID: mdl-29038275

RESUMEN

Antimicrobial resistance among uropathogens has increased the rates of infection-related morbidity and mortality. Antofloxacin is a novel fluoroquinolone with broad-spectrum antibacterial activity against urinary Gram-negative bacilli, such as Escherichia coli This study monitored the in vivo efficacy of antofloxacin using bioluminescent imaging and determined pharmacokinetic (PK)/pharmacodynamic (PD) targets against E. coli isolates in a neutropenic murine thigh infection model. The PK properties were determined after subcutaneous administration of antofloxacin at 2.5, 10, 40, and 160 mg/kg of body weight. Following thigh infection, the mice were treated with 2-fold-increasing doses of antofloxacin from 2.5 to 80 mg/kg administered every 12 h. Efficacy was assessed by quantitative determination of the bacterial burdens in thigh homogenates and was compared with the bioluminescent density. Antofloxacin demonstrated both static and killing endpoints in relation to the initial burden against all study strains. The PK/PD index area under the concentration-time curve (AUC)/MIC correlated well with efficacy (R2 = 0.92), and the dose-response relationship was relatively steep, as observed with escalating doses of antofloxacin. The mean free drug AUC/MIC targets necessary to produce net bacterial stasis and 1-log10 and 2-log10 kill for each isolate were 38.7, 66.1, and 147.0 h, respectively. In vivo bioluminescent imaging showed a rapid decrease in the bioluminescent density at free drug AUC/MIC exposures that exceeded the stasis targets. The integration of these PD targets combined with the results of PK studies with humans will be useful in setting optimal dosing regimens for the treatment of urinary tract infections due to E. coli.


Asunto(s)
Antibacterianos/farmacología , Infecciones por Escherichia coli/tratamiento farmacológico , Escherichia coli/efectos de los fármacos , Neutropenia/microbiología , Ofloxacino/análogos & derivados , Animales , Antibacterianos/administración & dosificación , Antibacterianos/farmacocinética , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Escherichia coli/genética , Escherichia coli/aislamiento & purificación , Femenino , Semivida , Ratones Endogámicos ICR , Pruebas de Sensibilidad Microbiana , Ofloxacino/administración & dosificación , Ofloxacino/farmacocinética , Ofloxacino/farmacología , Plásmidos/genética , Infecciones de los Tejidos Blandos/tratamiento farmacológico , Infecciones de los Tejidos Blandos/microbiología , Muslo/microbiología
7.
Artículo en Inglés | MEDLINE | ID: mdl-28264844

RESUMEN

Antofloxacin is a novel broad-spectrum fluoroquinolone under development for the treatment of infections caused by a diverse group of bacterial species. We explored the pharmacodynamic (PD) profile and targets of antofloxacin against seven Klebsiella pneumoniae isolates by using a neutropenic murine lung infection model. Plasma and bronchopulmonary pharmacokinetic (PK) studies were conducted at single subcutaneous doses of 2.5, 10, 40, and 160 mg/kg of body weight. Mice were infected intratracheally with K. pneumoniae and treated using 2-fold-increasing total doses of antofloxacin ranging from 2.5 to 160 mg/kg/24 h administered in 1, 2, 3, or 4 doses. The Emax Hill equation was used to model the dose-response data. Antofloxacin could penetrate the lung epithelial lining fluid (ELF) with pharmacokinetics similar to those in plasma with linear elimination half-lives over the dose range. All study strains showed a 3-log10 or greater reduction in bacterial burden and prolonged postantibiotic effects (PAEs) ranging from 3.2 to 5.3 h. Dose fractionation response curves were steep, and the free-drug area under the concentration-time curve over 24 h (AUC0-24)/MIC ratio was the PD index most closely linked to efficacy (R2 = 0.96). The mean free-drug AUC0-24/MIC ratios required to achieve net bacterial stasis, a 1-log10 kill, and a 2-log10 kill for each isolate were 52.6, 89.9, and 164.9, respectively. When integrated with human PK data, these PD targets could provide a framework for further optimization of dosing regimens. This could make antofloxacin an attractive option for the treatment of respiratory tract infections involving K. pneumoniae.


Asunto(s)
Antibacterianos/farmacocinética , Antibacterianos/uso terapéutico , Infecciones por Klebsiella/tratamiento farmacológico , Klebsiella pneumoniae/efectos de los fármacos , Ofloxacino/análogos & derivados , Infecciones del Sistema Respiratorio/tratamiento farmacológico , Animales , Femenino , Humanos , Klebsiella pneumoniae/aislamiento & purificación , Pulmón/microbiología , Ratones , Ratones Endogámicos ICR , Pruebas de Sensibilidad Microbiana , Neutropenia/tratamiento farmacológico , Neutropenia/microbiología , Ofloxacino/farmacocinética , Ofloxacino/uso terapéutico , Infecciones del Sistema Respiratorio/microbiología
8.
Vet Microbiol ; 192: 1-9, 2016 Aug 30.
Artículo en Inglés | MEDLINE | ID: mdl-27527758

RESUMEN

Horizontal transfer of plasmid-encoded multidrug-resistant determinants is a major health problem and has attracted much public attention. We studied the dissemination of the efflux pump gene oqxAB located on transferable plasmid pHXY0908 between Salmonella Typhimurium and Escherichia coli in the gut of chickens. After an inoculation with Salmonella Typhimurium harboring oqxAB-bearing plasmid pHXY0908, chickens were treated with enrofloxacin and florfenicol. Inoculated, but non-treated chickens were included as a control group. Our results revealed that commensal E. coli isolates from the gut of chickens acquired the oqxAB-bearing plasmid in both treated and non-treated groups. Additionally, in the florfenicol treatment group, the average isolation rate of oqxAB-positive E. coli was significantly higher than that in the non-treated group. PFGE analysis showed that oqxAB-positive E. coli strains belonged to different patterns with one predominating. Moreover, multilocus sequence typing analysis revealed that E. coli ST533 was closely associated with the spread of oqxAB gene. qPCR analysis indicated that antibiotic administration provided selective advantages for sustaining a significantly high level of oqxAB gene from the DNA extracted from the feces. There was also a fluctuation in the intestinal microbiota with antibiotic therapy. In conclusion, the present study indicates that the oqxAB gene could be readily spread within the intestinal microflora. This could be enhanced by administrated with clinical doses of florfenicol and enrofloxacin, resulting in the enlargement of resistance gene reservoirs. In addition, ST533 E. coli isolates were found to contribute to transfer of the oqxAB gene.


Asunto(s)
Pollos/microbiología , Farmacorresistencia Bacteriana Múltiple/genética , Escherichia coli/efectos de los fármacos , Fluoroquinolonas/farmacología , Salmonella typhimurium/efectos de los fármacos , Tianfenicol/análogos & derivados , Animales , Antibacterianos/farmacología , Cloaca/microbiología , ADN Bacteriano , Enrofloxacina , Escherichia coli/genética , Heces/microbiología , Regulación Bacteriana de la Expresión Génica , Transferencia de Gen Horizontal , Genes Bacterianos , Intestinos/microbiología , Pruebas de Sensibilidad Microbiana , Salmonella typhimurium/genética , Tianfenicol/farmacología
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