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1.
Sensors (Basel) ; 24(9)2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38732989

RESUMO

Due to the interaction of accumulated charges on the surface of a test mass with the surrounding electric and magnetic fields, the performance of inertial sensors is affected, necessitating charge management for the test mass. Discharge technology based on Ultraviolet LEDs is internationally recognized as the optimal solution for charge management. Precision driving of Ultraviolet LEDs is considered a key technology in charge management. This paper presents the driving control system used for Ultraviolet LEDs, achieving precision pulse-width-modulation-type current output with controllable pulse width and amplitude. The system generates the pulse-width-controllable pulse voltage signal via analog pulse-width modulation, and subsequently regulates the amplitude of the PWM signal through range switching. To convert the voltage into the pulse-width-modulation-type driving current, the improved Howland current source is employed. The test results demonstrate that the driving control system can output controllable current in the range of 0.01 mA to 10 mA, with a minimum step of 0.01 mA. The accuracy of the current reaches 1%, the stability within 1 h is better than 1%, and the load regulation is better than 2%. The driving control system provides an important reference for the integration of charge management system and the precision drive control method for LEDs.

2.
ACS Infect Dis ; 9(4): 801-814, 2023 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-36961435

RESUMO

Improving the efficacy of existing antibiotics is significant for combatting antibiotic resistance that poses a major threat to human health. Carbonyl cyanide m-chlorophenylhydrazine (CCCP), a well-known protonophore for dissipating proton motive force (PMF), has been widely used to block the PMF-dependent uptake of aminoglycoside antibiotics and thus suppress aminoglycoside lethality. Here, we report that CCCP and its functional analog FCCP, but not other types of protonophores, unprecedently potentiate aminoglycosides (e.g., tobramycin and gentamicin) by 3-4 orders of magnitude killing of Escherichia coli, Staphylococcus aureus, Shigella flexneri, and Vibrio alginolyticus cells in stationary phase but not these cells in exponential phase nor other 12 bacterial species we examined. Overall, the effect of CCCP on aminoglycoside lethality undergoes a gradual transition from suppression against E. coli exponential-phase cells to potentiation against late stationary-phase cells, with the cell growth status and culture medium being crucial. Consistently, disturbance of the PMF by changing transmembrane proton gradient (ΔpH) or electric potential (ΔΨ) also potentiates tobramycin. Nevertheless, CCCP neither increases the intracellular concentration of tobramycin nor decreases the MIC of the antibiotic, thus excluding that CCCP acts as an efflux pump inhibitor to potentiate aminoglycosides. Rather, we show that the combined treatment dramatically enhances the cellular level of hydroxyl radical under both aerobic and anaerobic culturing conditions, under which the antioxidant N-acetyl cysteine fully suppresses both hydroxyl radical accumulation and cell death. Together, these findings open a new avenue to develop certain protonophores as aminoglycoside adjuvants against pathogens in stationary phase and also illustrate an essential role of hydroxyl radical in aminoglycoside lethality regardless of aerobic respiration.


Assuntos
Aminoglicosídeos , Escherichia coli , Humanos , Aminoglicosídeos/farmacologia , Aminoglicosídeos/química , Carbonil Cianeto m-Clorofenil Hidrazona/farmacologia , Radical Hidroxila/farmacologia , Antibacterianos/farmacologia , Tobramicina/farmacologia
3.
Proc Natl Acad Sci U S A ; 120(12): e2217254120, 2023 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-36917671

RESUMO

The potentiation of antibiotics is a promising strategy for combatting antibiotic-resistant/tolerant bacteria. Herein, we report that a 5-min sublethal heat shock enhances the bactericidal actions of aminoglycoside antibiotics by six orders of magnitude against both exponential- and stationary-phase Escherichia coli. This combined treatment also effectively kills various E. coli persisters, E. coli clinical isolates, and numerous gram-negative but not gram-positive bacteria and enables aminoglycosides at 5% of minimum inhibitory concentrations to eradicate multidrug-resistant pathogens Acinetobacter baumannii and Klebsiella pneumoniae. Mechanistically, the potentiation is achieved comprehensively by heat shock-enhanced proton motive force that thus promotes the bacterial uptake of aminoglycosides, as well as by increasing irreversible protein aggregation and reactive oxygen species that further augment the downstream lethality of aminoglycosides. Consistently, protonophores, chemical chaperones, antioxidants, and anaerobic culturing abolish heat shock-enhanced aminoglycoside lethality. We also demonstrate as a proof of concept that infrared irradiation- or photothermal nanosphere-induced thermal treatments potentiate aminoglycoside killing of Pseudomonas aeruginosa in a mouse acute skin wound model. Our study advances the understanding of the mechanism of actions of aminoglycosides and demonstrates a high potential for thermal ablation in curing bacterial infections when combined with aminoglycosides.


Assuntos
Aminoglicosídeos , Antibacterianos , Camundongos , Animais , Antibacterianos/farmacologia , Antibacterianos/química , Aminoglicosídeos/farmacologia , Aminoglicosídeos/química , Espécies Reativas de Oxigênio/farmacologia , Agregados Proteicos , Escherichia coli , Bactérias Gram-Negativas , Bactérias , Resposta ao Choque Térmico , Testes de Sensibilidade Microbiana
4.
ACS Infect Dis ; 8(2): 373-386, 2022 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-35100802

RESUMO

Potentiation of traditional antibiotics is of significance for combating antibiotic-resistant bacteria that have become a severe threat to human and animal health. Here, we report that 1 min co-treatment with n-butanol greatly and specifically enhances the bactericidal action of aminoglycosides by 5 orders of magnitude against stationary-phase Staphylococcus aureus cells, with n-propanol and isobutanol showing less potency. This combined treatment also rapidly kills various S. aureus persisters, methicillin-resistant S. aureus (MRSA) cells, and numerous Gram-positive and -negative pathogens including some clinically isolated multidrug-resistant pathogens (e.g., S. aureus, Staphylococcus epidermidis, and Enterococcus faecalis) in vitro, as well as S. aureus in mice. Mechanistically, the potentiation results from the actions of aminoglycosides on their conventional target ribosome rather than the antiseptic effect of n-butanol and is achieved by rapidly enhancing the bacterial uptake of aminoglycosides, while salts and inhibitors of proton motive force (e.g., CCCP) can diminish this uptake. Importantly, such n-butanol-enhanced antibiotic uptake even enables subinhibitory concentrations of aminoglycosides to rapidly kill both MRSA and conventional S. aureus cells. Given n-butanol is a non-metabolite in the pathogens we tested, our work may open avenues to develop a metabolite-independent strategy for aminoglycoside potentiation to rapidly eliminate antibiotic-resistant/tolerant pathogens, as well as for reducing the toxicity associated with aminoglycoside use.


Assuntos
Aminoglicosídeos , Staphylococcus aureus Resistente à Meticilina , 1-Butanol/farmacologia , Aminoglicosídeos/farmacologia , Animais , Antibacterianos/farmacologia , Camundongos , Testes de Sensibilidade Microbiana , Staphylococcus aureus , Staphylococcus epidermidis
5.
Antimicrob Agents Chemother ; 66(2): e0112521, 2022 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-34902270

RESUMO

Improving the efficacy of existing antibiotics is a promising strategy for combating antibiotic-resistant/tolerant bacterial pathogens that have become a severe threat to human health. We previously reported that aminoglycoside antibiotics could be dramatically potentiated against stationary-phase Escherichia coli cells under hypoionic shock conditions (i.e., treatment with ion-free solutions), but the underlying molecular mechanism remains unknown. Here, we show that mechanosensitive (MS) channels, a ubiquitous protein family sensing mechanical forces of cell membrane, mediate such hypoionic shock-induced aminoglycoside potentiation. Two-minute treatment under conditions of hypoionic shock (e.g., in pure water) greatly enhances the bactericidal effects of aminoglycosides against both spontaneous and triggered E. coli persisters, numerous strains of Gram-negative pathogens in vitro, and Pseudomonas aeruginosa in mice. Such potentiation is achieved by hypoionic shock-enhanced bacterial uptake of aminoglycosides and is linked to hypoionic shock-induced destabilization of the cytoplasmic membrane in E. coli. Genetic and biochemical analyses reveal that MscS-family channels directly and redundantly mediate aminoglycoside uptake upon hypoionic shock and thus potentiation, with MscL channel showing reduced effect. Molecular docking and site-directed mutagenesis analyses reveal a putative streptomycin-binding pocket in MscS, critical for streptomycin uptake and potentiation. These results suggest that hypoionic shock treatment destabilizes the cytoplasmic membrane and thus changes the membrane tension, which immediately activates MS channels that are able to effectively transport aminoglycosides into the cytoplasm for downstream killing. Our findings reveal the biological effects of hypoionic shock on bacteria and can help to develop novel adjuvants for aminoglycoside potentiation to combat bacterial pathogens via activating MS channels.


Assuntos
Aminoglicosídeos , Proteínas de Escherichia coli , Aminoglicosídeos/química , Aminoglicosídeos/farmacologia , Animais , Antibacterianos/farmacologia , Bactérias , Escherichia coli , Proteínas de Escherichia coli/genética , Canais Iônicos , Camundongos , Simulação de Acoplamento Molecular
7.
Artigo em Inglês | MEDLINE | ID: mdl-32185144

RESUMO

Antibiotic resistance/tolerance has become a severe threat to human and animal health. To combat antibiotic-resistant/tolerant bacteria, it is of significance to improve the efficacy of traditional antibiotics. Here we show that indole potentiates tobramycin to kill stationary-phase Staphylococcus aureus cells after a short, combined treatment, with its derivative 5-methylindole being the most potent compound tested and with the absence of ions as a prerequisite. Consistently, this combined treatment also kills various types of S. aureus persister cells as induced by the protonophore CCCP, nutrient shift, or starvation, as well as methicillin-resistant S. aureus (MRSA) cells. Importantly, 5-methylindole potentiates tobramycin killing of S. aureus persisters in a mouse acute skin wound model. Furthermore, 5-methylindole facilitates killing of many strains of gram-positive pathogens such as Staphylococcus epidermidis, Enterococcus faecalis, and Streptococcus pyogenes by aminoglycoside antibiotics, whereas it suppresses the action of aminoglycoside against the gram-negative pathogens Escherichia coli and Shigella flexneri. In conclusion, our work may pave the way for the development of indole derivatives as adjuvants to potentiate aminoglycosides against gram-positive pathogens.


Assuntos
Aminoglicosídeos/uso terapêutico , Indóis/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Tobramicina/farmacologia , Trifosfato de Adenosina/metabolismo , Animais , Antibacterianos/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Farmacorresistência Bacteriana Múltipla , Sinergismo Farmacológico , Quimioterapia Combinada , Enterococcus faecalis/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana , Pressão Osmótica , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus epidermidis/efeitos dos fármacos , Streptococcus pyogenes/efeitos dos fármacos , Cicatrização
8.
mBio ; 11(1)2020 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-32047133

RESUMO

Bacterial persisters exhibit noninherited antibiotic tolerance and are linked to the recalcitrance of bacterial infections. It is very urgent but also challenging to develop antipersister strategies. Here, we report that 10-s freezing with liquid nitrogen dramatically enhances the bactericidal action of aminoglycoside antibiotics by 2 to 6 orders of magnitude against many Gram-negative pathogens, with weaker potentiation effects on Gram-positive bacteria. In particular, antibiotic-tolerant Escherichia coli and Pseudomonas aeruginosa persisters-which were prepared by treating exponential-phase cells with ampicillin, ofloxacin, the protonophore cyanide m-chlorophenyl hydrazone (CCCP), or bacteriostatic antibiotics-can be effectively killed. We demonstrated, as a proof of concept, that freezing potentiated the aminoglycosides' killing of P. aeruginosa persisters in a mouse acute skin wound model. Mechanistically, freezing dramatically increased the bacterial uptake of aminoglycosides regardless of the presence of CCCP, indicating that the effects are independent of the proton motive force (PMF). In line with these results, we found that the effects were linked to freezing-induced cell membrane damage and were attributable, at least partly, to the mechanosensitive ion channel MscL, which was able to directly mediate such freezing-enhanced aminoglycoside uptake. In view of these results, we propose that the freezing-induced aminoglycoside potentiation is achieved by freezing-induced cell membrane destabilization, which, in turn, activates the MscL channel, which is able to effectively take up aminoglycosides in a PMF-independent manner. Our work may pave the way for the development of antipersister strategies that utilize the same mechanism as freezing but do so without causing any injury to animal cells.IMPORTANCE Antibiotics have long been used to successfully kill bacterial pathogens, but antibiotic resistance/tolerance usually has led to the failure of antibiotic therapy, and it has become a severe threat to human health. How to improve the efficacy of existing antibiotics is of importance for combating antibiotic-resistant/tolerant pathogens. Here, we report that 10-s rapid freezing with liquid nitrogen dramatically enhanced the bactericidal action of aminoglycoside antibiotics by 2 to 6 orders of magnitude against many bacterial pathogens in vitro and also in a mouse skin wound model. In particular, such combined treatment was able to effectively kill persister cells of Escherichia coli and Pseudomonas aeruginosa, which are per se tolerant of conventional treatment with bactericidal antibiotics for several hours. We also demonstrated that freezing-induced aminoglycoside potentiation was apparently linked to freezing-induced cell membrane damage that may have activated the mechanosensitive ion channel MscL, which, in turn, was able to effectively uptake aminoglycoside antibiotics in a proton motive force-independent manner. Our report sheds light on the development of a new strategy against bacterial pathogens by combining existing antibiotics with a conventional physical treatment or with MscL agonists.


Assuntos
Aminoglicosídeos/farmacologia , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Congelamento , Aminoglicosídeos/química , Animais , Bactérias/crescimento & desenvolvimento , Biofilmes/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Proteínas de Escherichia coli/metabolismo , Canais Iônicos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana , Nitrogênio/farmacologia , Força Próton-Motriz , Pseudomonas aeruginosa/efeitos dos fármacos , Pele/efeitos dos fármacos , Pele/microbiologia
9.
Front Microbiol ; 10: 2028, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31551965

RESUMO

Bacterial persister cells are phenotypic variants that exhibit transient antibiotic tolerance and play a leading role in chronic infections and the development of antibiotic resistance. Determining the mechanism that underlies persister formation and developing anti-persister strategies, therefore, are clinically important goals. Here, we report that many gram-negative and gram-positive bacteria become highly tolerant to typical bactericidal antibiotics when the carbon source for their antibiotic-sensitive exponential growth phase is shifted to fumarate, suggesting a role for fumarate in persister induction. Nutrient shift-induced Escherichia coli but not Staphylococcus aureus persister cells can be killed by aminoglycosides upon hypoionic shock (i.e., the absence of ions), which is achieved by suspending the persisters in aminoglycoside-containing pure water for only 1 or 2 min. Such potentiation can be abolished by inhibitors of the electron transport chain (e.g., NaN3) or proton motive force (e.g., CCCP). Additionally, we show that hypoionic shock facilitates the eradication of starvation-induced E. coli but not S. aureus persisters by aminoglycosides, and that such potentiation can be significantly suppressed by NaN3 or CCCP. Mechanistically, hypoionic shock dramatically enhances aminoglycoside uptake by both nutrient shift- and starvation-induced E. coli persisters, whereas CCCP can diminish this uptake. Results of our study illustrate the general role of fumarate in bacterial persistence and may open new avenues for persister eradication and aminoglycoside use.

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