RESUMO
The lack of therapeutic options to treat infections caused by multidrug-resistant (MDR) pathogens, especially Gram-negative bacteria, is apparent. Therefore, it is imperative to develop new strategies to address the problem of antimicrobial resistance. Repurposing non-antibiotic commercial drugs for antimicrobial therapy presents a viable option. We screened six anticancer drugs for their potential use in antimicrobial therapy. Here, we provide in vitro evidence that suggests feasibility to repurpose the anticancer drug mitomycin C against MDR Gram-negative bacteria. We also demonstrated that mitomycin C, etoposide and doxorubicin were affected by drug efflux in Pseudomonas aeruginosa. In combination with a tobramycin-ciprofloxacin antibiotic hybrid (TOB-CIP), the antibacterial activity of mitomycin C was enhanced against MDR clinical isolates of P. aeruginosa, Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae. In fact, 4 µg/mL (3 µM) TOB-CIP reduced the minimum inhibitory concentration of mitomycin C to ≤1 µg/mL against MDR Gram-negative bacteria, except A. baumannii. We showed that synergy was inherent to TOB-CIP and that neither tobramycin nor ciprofloxacin individually synergized with mitomycin C. Our finding supports identifying adjuvant partners for mitomycin C, such as TOB-CIP, to enhance suitability for antimicrobial therapy.
RESUMO
Chromosomally encoded low membrane permeability and highly efficient efflux systems are major mechanisms by which Pseudomonas aeruginosa evades antibiotic actions. Our previous reports have shown that amphiphilic tobramycin-fluoroquinolone hybrids can enhance efficacy of fluoroquinolone antibiotics against multidrug-resistant (MDR) P. aeruginosa isolates. Herein, we report on a novel class of tobramycin-lysine conjugates containing an optimized amphiphilic tobramycin-C12 tether that sensitize Gram-negative bacteria to legacy antibiotics. Combination studies indicate the ability of these conjugates to synergize rifampicin and minocycline against MDR and extensively drug resistant (XDR) P. aeruginosa isolates and enhance efficacy of both antibiotics in the Galleria mellonella larvae in vivo infection model. Mode of action studies indicate that the amphiphilic tobramycin-lysine adjuvants enhance outer membrane cell penetration and affect the proton motive force, which energizes efflux pumps. Overall, this study provides a strategy for generating effective antibiotic adjuvants that overcome resistance of rifampicin and minocycline in MDR and XDR Gram-negative bacteria including P. aeruginosa.
Assuntos
Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Lisina/química , Minociclina/farmacologia , Rifampina/farmacologia , Tobramicina/farmacologia , Antibacterianos/química , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Hemólise/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Modelos Biológicos , Tobramicina/químicaRESUMO
Drug efflux mechanisms interact synergistically with the outer membrane permeability barrier of Gram-negative bacteria, leading to intrinsic resistance that presents a major challenge for antibiotic drug development. Efflux pump inhibitors (EPIs) which block the efflux of antibiotics synergize antibiotics, but the clinical development of EPI/antibiotic combination therapy to treat multidrug-resistant (MDR) Gram-negative infections has been challenging. This is in part caused by the inefficiency of current EPIs to penetrate the outer membrane and resist efflux. We demonstrate that conjugation of a tobramycin (TOB) vector to EPIs like NMP, paroxetine, or DBP enhances synergy and efficacy of EPIs in combination with tetracycline antibiotics against MDR Gram-negative bacteria including Pseudomonas aeruginosa. Besides potentiating tetracycline antibiotics, TOB-EPI conjugates can also suppress resistance development to the tetracycline antibiotic minocycline, thereby providing a strategy to develop more effective adjuvants to rescue tetracycline antibiotics from resistance in MDR Gram-negative bacteria.
Assuntos
Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Proteínas de Membrana Transportadoras/metabolismo , Tobramicina/farmacologia , Bactérias Gram-Positivas/efeitos dos fármacosRESUMO
Therapeutic interventions to treat multidrug-resistant (MDR) Pseudomonas aeruginosa infections are severely limited and often require the use of colistin as drug of last resort. The major challenges impeding the development of novel antipseudomonal agents are the lack of cell penetration and extensive efflux. We have discovered a tobramycin-moxifloxacin hybrid core structure which enhances outer membrane permeability and reduces efflux by dissipating the proton motive force of the cytoplasmic membrane in P. aeruginosa. The optimized hybrid protects Galleria mellonella larvae from the lethal effects of MDR P. aeruginosa. Attempts to select for resistance over a period of 25 days resulted in a 2-fold increase in the minimal inhibitory concentration (MIC) for the hybrid, while moxifloxacin or tobramycin resulted in a 16- and 512-fold increase in MIC. Although the hybrid possesses potent activity against MDR, P. aeruginosa isolates the activity that can be synergized when used in combination with other classes of antibiotics.
Assuntos
Antibacterianos/farmacologia , Fluoroquinolonas/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Tobramicina/farmacologia , Antibacterianos/química , Farmacorresistência Bacteriana Múltipla , Fluoroquinolonas/química , Humanos , Moxifloxacina , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/citologia , Tobramicina/análogos & derivadosRESUMO
The use of adjuvants that rescue antibiotics against multidrug-resistant (MDR) pathogens is a promising combination strategy for overcoming bacterial resistance. While the combination of ß-lactam antibiotics and ß-lactamase inhibitors has been successful in restoring antibacterial efficacy in MDR bacteria, the use of adjuvants to restore fluoroquinolone efficacy in MDR Gram-negative pathogens has been challenging. We describe tobramycin-ciprofloxacin hybrid adjuvants that rescue the activity of fluoroquinolone antibiotics against MDR and extremely drug-resistant Pseudomonas aeruginosa isolates inâ vitro and enhance fluoroquinolone efficacy inâ vivo. Structure-activity studies reveal that the presence of both tobramycin and ciprofloxacin, which are separated by a C12 tether, is critical for the function of the adjuvant. Mechanistic studies indicate that the antibacterial modes of ciprofloxacin are retained while the role of tobramycin is limited to destabilization of the outer membrane in the hybrid.
Assuntos
Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla , Fluoroquinolonas/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Testes de Sensibilidade MicrobianaRESUMO
A low-cost and highly sensitive biosensor system is designed to investigate carbohydrate-lectin interactions. This combination of glyco-gold nanoparticles and boronic acid biosensor system opens a way to study noncovalent drug delivery.
Assuntos
Técnicas Biossensoriais , Carboidratos/química , Sistemas de Liberação de Medicamentos , Lectinas/química , Nanopartículas , Espectrometria de FluorescênciaRESUMO
An efficient, base-free protocol has been developed for the ß-stereoselective synthesis of N-glycosides from 2-nitroglycal and secondary amines. Simple protection and deprotection manipulations on the N-glycosides pave a way for the synthesis of biologically significant1,2-diaminosugars and glycopeptides.
Assuntos
Glucosamina/análogos & derivados , Glicosídeos/química , Glicosídeos/síntese química , Cristalografia por Raios X , Glucosamina/química , Modelos Moleculares , Estrutura Molecular , EstereoisomerismoRESUMO
Carbohydrate-integrated isoxazolines were synthesized from 2-nitroglycals and sulfur ylides, with the aid of 1-phenylthiourea catalyst. The reactions proceeded via [4+1] annulations and upon subsequent rearrangement, afforded the corresponding isoxazolines in high yields with excellent diastereoselectivities (up to 95% de).
Assuntos
Carboidratos/química , Isoxazóis/química , Isoxazóis/síntese química , Catálise , Cristalografia por Raios X , Ciclização , Conformação Molecular , Feniltioureia/química , EstereoisomerismoRESUMO
A highly stereoselective BF(3)·OEt(2)-promoted tandem hydroamination-glycosylation on a glycal scaffold has been developed to form 3-amino-2,3-dideoxysugars in a one-pot procedure. This efficient multicomponent reaction protocol offers simplicity and general applicability to a broad range of variations on each component.
Assuntos
Carboidratos/química , Éteres Cíclicos/química , Aminação , Glicosilação , Estereoisomerismo , Especificidade por SubstratoRESUMO
Pyrrolidine derivatives were prepared in high diastereoselectivities and good yields via a [3 + 2] cycloaddition of a tert-butyldimethylsilyl protected carbohydrate-based allene with a diverse range of imines. The subsequent removal of the carbohydrate auxiliary afforded a variety of pyrrolidines with excellent enantioselectivities (up to 99% ee). Selective reduction of the pyrrolidines further demonstrated the potential of this strategy.
Assuntos
Carboidratos/química , Pirrolidinas/síntese química , Catálise , Estrutura Molecular , Oxirredução , Pirrolidinas/química , Silanos/química , EstereoisomerismoRESUMO
A direct and efficient approach to 1-aminoindolizines through three-component one-pot reaction of heteroaryl aldehydes, secondary amines, and terminal alkynes catalyzed by AgBF(4) has been developed. Desired products were obtained in moderate to excellent yields. Similar aminoindolizines products were afforded from trimethylsilyl protected alkyne substrates as well. This methodology provides a rapid access to construct a diversity-oriented library of indolizines.
Assuntos
Técnicas de Química Combinatória , Compostos Heterocíclicos/síntese química , Indolizinas/síntese química , Compostos Organometálicos/química , Prata/química , Aldeídos/química , Alcinos/química , Aminas/química , Catálise , Compostos Heterocíclicos/química , Indolizinas/química , Estrutura Molecular , EstereoisomerismoRESUMO
Carbon nanotubes (CNTs) have attracted tremendous attention in biomedical applications due to their molecular size and unique properties. This tutorial review summarizes the strategies to functionalize CNTs with bioactive carbohydrates, which improve their solubility, biocompatibility and biofunctionalities while preserving their desired properties. In addition, studies on the usage of carbohydrate functionalized CNTs to detect bacteria, to bind to specific lectins, to deliver glycomimetic drug molecules into cells and to probe cellular activities as biosensors are reviewed. Improvement in biocompatibility and introduction of bio-functionalities by integration of carbohydrate with CNTs are paving the way to glyconanotechnology and may provide new tools for glycobiological studies.
Assuntos
Carboidratos/química , Nanotubos de Carbono/química , Animais , Bactérias/metabolismo , Técnicas Biossensoriais , Linhagem Celular , Humanos , Nanomedicina , Proteínas/metabolismoRESUMO
An immense effort has been made to develop an efficient strategy for the carbon-carbon bond formation between aldehyde and nitrile intramolecularly using an N-heterocyclic carbene catalyst to derive 3-aminochromone derivatives in good to excellent yields (80-95%).
Assuntos
Aldeídos/química , Cromonas/química , Compostos Heterocíclicos/química , Metano/análogos & derivados , Nitrilas/química , Catálise , Metano/química , Estrutura MolecularRESUMO
A general and diastereoselective synthesis of (2S, 4S)-4-mercapto-L-lysine derivative was described. The key features of this synthesis include Zn-mediated diastereoselective Reformatsky reaction and selective reduction of methyl ester with sodium borohydride. Introduction of thiol functional group on lysine side chain proved to be appropriate for dual native chemical ligation. This methodology allows to develop various 4-substituted L-lysine derivatives.
Assuntos
Antivirais/síntese química , Lisina/química , Preparações Farmacêuticas/síntese química , Catálise , Cristalografia por Raios X , Ésteres/química , Lisina/análogos & derivados , Fragmentos de Peptídeos/química , Preparações Farmacêuticas/química , Compostos de Sulfidrila/químicaRESUMO
A mild and efficient synthesis of pseudoglycosides has been developed using metal free (S)-camphorsulfonic acid. (S)-CSA acts as an excellent catalyst for conversion of 2,4,6-tri-O-acetyl-D-glucal to 2,3-unsaturated O-glycosides. A wide range of biologically active natural products, alcohols and thiols could be coupled with glucal to give the desired pseudoglycosides in good to excellent yields with exclusive alpha-stereoselectivity.