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Synergistic antibacterial activity of silver with antibiotics correlating with the upregulation of the ROS production.

ABSTRACT: Thiol-dependent enzymes, including the thioredoxin (Trx) and glutathione (GSH) systems, have recently been found as promising bactericidal targets in multidrug-resistant (MDR) bacteria. We previously discovered that silver acted synergistically with ebselen in the inhibition of the Trx system and also resulted in a fast depletion of GSH in Gram-negative bacteria. Silver has been found by others to improve the sensitivity of bacteria to certain conventional antibiotics. Here, we found that the synergistic antibacterial effects of silver with four conventional antibiotics was correlated with the blockage of bacterial Trx system by silver. The synergistic antibacterial effect came along with the production of reactive oxygen species. All these results suggested that silver primarily enhanced the bactericidal activities of conventional antibiotics towards Gram-negative strains through the upregulation of ROS production.

SUBMITTER: Zou L

PROVIDER: S-EPMC6057937 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Synergistic antibacterial activity of silver with antibiotics correlating with the upregulation of the ROS production.

Zou Lili L Wang Jun J Gao Yu Y Ren Xiaoyuan X Rottenberg Martin E ME Lu Jun J Holmgren Arne A

Scientific reports 20180724 1

Thiol-dependent enzymes, including the thioredoxin (Trx) and glutathione (GSH) systems, have recently been found as promising bactericidal targets in multidrug-resistant (MDR) bacteria. We previously discovered that silver acted synergistically with ebselen in the inhibition of the Trx system and also resulted in a fast depletion of GSH in Gram-negative bacteria. Silver has been found by others to improve the sensitivity of bacteria to certain conventional antibiotics. Here, we found that the sy ...[more]

PMID: 30042429

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Project description:The devastating antibacterial infections, coupled with their antibiotic resistance abilities, emphasize the need for effective antibacterial therapeutics. In this prospect, liposomal delivery systems have been employed in improving the efficacy of the antibacterial agents. The liposome-based antibiotics enhance the therapeutic potential of the new or existing antibiotics and reduce their adverse effects. The current study describes the development of sulfonium-based antibacterial lipids that demonstrate the delivery of existing antibiotics. The presence of cationic sulfonium moieties and inherent membrane targeting abilities of the lipids could help reduce the antibiotic resistance abilities of the bacteria and deliver the antibiotics to remove the infectious pathogens electively. The transmission electron microscopic images and dynamic light scattering analyses revealed the liposome formation abilities of the sulfonium-based amphiphilic compounds in the aqueous medium. The effectiveness of the compounds was tested against the Gram-negative and Gram-positive bacterial strains. The viability of the bacterial cells was remarkably reduced in the presence of the compounds. The sulfonium-based compounds with pyridinium moiety and long hydrocarbon chains showed the most potent antibacterial activities among the tested compounds. Mechanistic studies revealed the membrane-targeted bactericidal activities of the compounds. The potent compound also showed tetracycline and amoxicillin encapsulation and sustained release profiles in the physiologically relevant medium. The tetracycline and amoxicillin-encapsulated lipid showed much higher antibacterial activities than the free antibiotics at similar concentrations, emphasizing the usefulness of the synergistic effect of sulfonium-based lipid and the antibiotics, signifying that the sulfonium lipid penetrated the bacterial membrane and increased the cellular uptake of the antibiotics. The potent lipid also showed therapeutic potential, as it is less toxic to mammalian cells (like HeLa and HaCaT cells) at concentrations higher than their minimum inhibitory concentration values against S. aureus, E. coli, and MRSA. Hence, the sulfonium-based lipid exemplifies a promising framework for assimilating various warheads, and provides a potent antibacterial material.

Project description:Nanotechnology is being investigated for its potential to improve nanomedicine for human health. The purpose of this study was to isolate carbapenemase-producing Gram-negative bacilli (CPGB), investigate the presence of carbapenemase resistance genes, determine their antibiogram and ability to biosynthesise silver nanoparticles (Ag NPs), and estimate the antibacterial activity of Acinetobacter baumannii-biosynthesised Ag NPs on CPGB alone and in combination with antibiotics. A total of 51 CPGBs were isolated from various specimens in the study. The automated Vitek-2 system was used to identify and test these strains' antimicrobial susceptibilities. The carbapenemase resistance genes were identified using a polymerase chain reaction (PCR). Under the CPGB, A. baumannii could biosynthesise Ag NPs. X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FT-IR), transmission electron microscopy (TEM), and field emission scanning electron were used to characterise Ag NPs. The antibacterial activity of Ag NP alone and in combination with antibiotics against CPGB was determined using the broth microdilution method, and their synergistic effect was determined using the checkerboard assay. bla NDM and bla OXA-48 were the most commonly reported, and 90% of the isolates produced multiple carbapenemase genes. Tigecycline proved to be the most effective anti-CPGB antibiotic. Isolates with more resistance genes were more resistant to antibiotics, and isolates with three genes (42%) had the most extensively drug-resistant patterns (38%). A significant relationship was discovered between genetic and antibiotic resistance patterns. Only A. baumannii produced Ag NPs out of all the isolates tested. Ag NPs with a size of 10 nm were confirmed by UV-visible spectroscopy, FT-IR, XRD, and TEM analysis. The Ag NPs were effective against CPGB, with minimum inhibitory concentrations ranging from 64 to 8 μg/ml on average. Surprisingly, the combination of Ag NPs and antibiotics demonstrated synergistic and partial synergistic activity (fractional inhibitory concentration between 0.13 and 0.56) against CPGB, as well as a significant reduction in antibiotic concentrations, particularly in the case of A. baumanii versus ceftriaxone (1024 to 4 μg/ml). The notable synergistic activity of Ag NPs with antibiotics represents a valuable nanomedicine that may find clinical application in the future as a combined remedy.

Project description:Multidrug resistance among various bacterial strains is leading to worldwide resistance to a wide range of antibiotics. Combination therapy involving current antibiotics and other biological or chemical molecules represents an attractive novel strategy. In this study, we investigated the synergistic antibacterial activity of a series of Trp-containing antimicrobial peptides (AMPs) with four classes of traditional chemical antibiotics that are inactive against multidrug-resistant Staphylococcus epidermidis (MRSE) in vitro and in vivo. Among the antibiotics that we studied, penicillin, ampicillin and erythromycin showed a distinct synergistic effect in combination with all of the Trp-containing AMPs, represented by a fractional inhibitory concentration index (FICI) of <0.5. The antibacterial activities were noticeably improved, with 32-to 64-fold reductions in the MIC values for ampicillin and 16- to 32-fold reductions in the MIC values for erythromycin and penicillin. Tetracycline showed synergistic activity with only I1WL5W but additive activity with L11W, L12W, and I4WL5W. Ceftazidime exhibited additive activity with the Trp-containing peptides. In addition, the antibiotics in combination with the peptide significantly inhibited biofilm formation by MRSE 1208. A mechanistic study demonstrated that the Trp-containing peptides, especially I1WL5W and I4WL5W, which contain two tryptophan residues, disrupted bacterial inner and outer membranes, which promoted antibiotic delivery into the cytoplasm and access to cytoplasmic targets; however, L11W and L12W may have increased intracellular antibiotic concentrations by decreasing blaZ, tet(m) and msrA expression. Importantly, strong synergistic activity against the MRSE 1208 strain was observed for the combination of I1WL5W and penicillin in a mouse infection model. Thus, the combination of AMPs and traditional antibiotics could be a promising option for the prevention of acute and chronic infections caused by MRSE.

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Synergistic antibacterial activity of silver with antibiotics correlating with the upregulation of the ROS production.

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Synergistic antibacterial activity of silver with antibiotics correlating with the upregulation of the ROS production.

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