scholarly journals Inhibiting the copper efflux system in microbes as a novel approach for developing antibiotics

2019 ◽  
Author(s):  
Aviv Meir ◽  
Veronica Lepechkin-Zilbermintz ◽  
Shirin Kahremany ◽  
Fabian Schwerdtfeger ◽  
Lada Gevorkyan-Airapetov ◽  
...  
Keyword(s):  
Adaptor Protein ◽  
Copper Stress ◽  
Proper Function ◽  
Resistant Bacteria ◽  
Regulation System ◽  
Efflux System ◽  
Copper Transporter ◽  
Copper Transporters ◽  
Novel Approach ◽  
Novel Antibiotics

AbstractFive out of six people receive at least one antibiotic prescription per year. However, the ever-expanding use of antibiotics in medicine, agriculture, and food production has accelerated the evolution of antibiotic-resistant bacteria, which, in turn, made the development of novel antibiotics based on new molecular targets a priority in medicinal chemistry. One way of possibly combatting resistant bacterial infections is by inhibiting the copper transporters in prokaryotic cells. Copper is a key element within all living cells, but it can be toxic in excess. Both eukaryotic and prokaryotic cells have developed distinct copper regulation systems to prevent its toxicity. Therefore, selectively targeting the prokaryotic copper regulation system might be an initial step in developing next-generation antibiotics. One such system is the Gram-negative bacterial CusCFBA efflux system. CusB is a key protein in this system and was previously reported to play an important role in opening the channel for efflux via significant structural changes upon copper binding while also controlling the assembly and disassembly process of the entire channel. In this study, we aimed to develop novel peptide copper channel blockers, designed by in silico calculations based on the structure of CusB. Using a combination of magnetic resonance spectroscopy and various biochemical methods, we found a lead peptide that promotes copper-induced cell toxicity. Targeting copper transport in bacteria has not yet been pursued as an antibiotic mechanism of action. Thus, our study lays the foundation for discovering novel antibiotics.Author SummaryHerein, we apply a novel approach for the development of a new generation of antibiotics based on copper toxicity. In cells, copper ions are double-edge swords. On the one hand, various enzymes depend on them as cofactors for catalysis, but on the other hand, they are highly toxic. Thus, cells have developed sophisticated regulation systems to very precisely control copper concentration. Prokaryotic organisms are more sensitive to copper than eukaryotic systems, and therefore they employ additional copper transporters that have no homology in the eukaryotic cells in general and specifically in the human cell. Here, we suggest to take advantage of this fact, by developing inhibitors against one of the bacterial copper transporter: CusCBA. The adaptor protein within this transporter, CusB, plays a critical role in the opening of the whole transporter. We designed a peptide that interfere with its proper function and assembly, and therefore inhibits the opening of the transporter upon copper stress. This study lays the foundation for designing better and novel antibiotics.

Novel Antibiotics from Marine Sources

2011 ◽  
Vol 4 (3) ◽  
pp. 1446-1461 ◽  
Author(s):  
E.A. Martis ◽  
G M Doshi ◽  
G V Aggarwal ◽  
P P Shanbhag
Keyword(s):  
Pharmaceutical Industry ◽  
Resistant Bacteria ◽  
Drug Resistant ◽  
Drug Resistant Bacteria ◽  
Terrestrial Life ◽  
New Antibiotics ◽  
Antibiotic Compounds ◽  
New Generation ◽  
Novel Antibiotics ◽  
Untapped Resource

With the emergence of newer diseases, resistant forms of infectious diseases and multi-drug resistant bacteria, it has become essential to develop novel and more effective antibiotics. Current antibiotics are obtained from terrestrial life or made synthetically from intermediates. The ocean represents virtually untapped resource from which novel antibiotic compounds can be discovered. It is the marine world that will provide the pharmaceutical industry with the next generation of antibiotics. Marine antibiotics are antibiotics obtained from marine organisms. Scientists have reported the discovery of various antibiotics from marine bacteria (aplasmomycin, himalomycins, and pelagiomycins), sponges (Ara C, variabillin, strobilin, ircinin-1, aeroplysin, 3,5-dibromo-4-hydroxyphenylacetamide), coelenterates (asperidol and eunicin), mollusks (laurinterol and pachydictyol), tunicates (geranylhydroquinone and cystadytins), algae (cycloeudesmol, aeroplysinin-1(+), prepacifenol and tetrabromoheptanone), worms (tholepin and 3,5-dibromo-4-hydroxybezaldehyde), and actinomycetes (marinomycins C and D). This indicates that the marine environment, representing approximately half of the global diversity, is an enormous resource for new antibiotics and this source needs to be explored for the discovery of new generation antibiotics. The present article provides an overview of various antibiotics obtained from marine sources.

scholarly journals The Synergistic Effect of Biosynthesized Silver Nanoparticles and Phage ZCSE2 as a Novel Approach to Combat Multidrug-Resistant Salmonella enterica

Antibiotics ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 678
Author(s):  
Abdallah S. Abdelsattar ◽  
Rana Nofal ◽  
Salsabil Makky ◽  
Anan Safwat ◽  
Amera Taha ◽  
...  
Keyword(s):  
Silver Nanoparticles ◽  
Color Change ◽  
Antibacterial Properties ◽  
Multidrug Resistant ◽  
Inhibitory Effect ◽  
Health Concern ◽  
Resistant Bacteria ◽  
Mortality And Morbidity ◽  
Novel Approach ◽  
Transmission Electron

The emergence and evolution of antibiotic-resistant bacteria is considered a public health concern. Salmonella is one of the most common pathogens that cause high mortality and morbidity rates in humans, animals, and poultry annually. In this work, we developed a combination of silver nanoparticles (AgNPs) with bacteriophage (phage) as an antimicrobial agent to control microbial growth. The synthesized AgNPs with propolis were characterized by testing their color change from transparent to deep brown by transmission electron microscopy (TEM) and Fourier-Transform Infrared Spectroscopy (FTIR). The phage ZCSE2 was found to be stable when combined with AgNPs. Both minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were evaluated for AgNPs, phage, and their combination. The results indicated that MIC and MBC values were equal to 23 µg/mL against Salmonella bacteria at a concentration of 107 CFU/mL. The combination of 0.4× MIC from AgNPs and phage with Multiplicity of Infection (MOI) 0.1 showed an inhibitory effect. This combination of AgNPs and phage offers a prospect of nanoparticles with significantly enhanced antibacterial properties and therapeutic performance.

Antibiotic-Resistant Bacteria and the Use of Novel Antibiotics in Children

2018 ◽  
Vol 47 (9) ◽  
pp. e354-e358 ◽  
Author(s):  
Evelyn Lai ◽  
Jeffrey M. Bender
Keyword(s):  
Resistant Bacteria ◽  
Antibiotic Resistant Bacteria ◽  
Antibiotic Resistant ◽  
Novel Antibiotics

scholarly journals Characterization of the Copper Transporters from Lotus spp. and Their Involvement under Flooding Conditions

2019 ◽  
Vol 20 (13) ◽  
pp. 3136 ◽  
Author(s):  
Francisco J. Escaray ◽  
Cristian J. Antonelli ◽  
Guillermo J. Copello ◽  
Sergi Puig ◽  
Lola Peñarrubia ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Higher Plants ◽  
Economic Losses ◽  
Copper Uptake ◽  
Copper Transporter ◽  
Copper Transporters ◽  
Transporter Family ◽  
Adaptive Mechanisms ◽  
High Prevalence ◽  
Natural Grassland

Forage legumes are an important livestock nutritional resource, which includes essential metals, such as copper. Particularly, the high prevalence of hypocuprosis causes important economic losses to Argentinian cattle agrosystems. Copper deficiency in cattle is partially due to its low content in forage produced by natural grassland, and is exacerbated by flooding conditions. Previous results indicated that incorporation of Lotus spp. into natural grassland increases forage nutritional quality, including higher copper levels. However, the biological processes and molecular mechanisms involved in copper uptake by Lotus spp. remain poorly understood. Here, we identify four genes that encode putative members of the Lotus copper transporter family, denoted COPT in higher plants. A heterologous functional complementation assay of the Saccharomyces cerevisiae ctr1∆ctr3∆ strain, which lacks the corresponding yeast copper transporters, with the putative Lotus COPT proteins shows a partial rescue of the yeast phenotypes in restrictive media. Under partial submergence conditions, the copper content of L. japonicus plants decreases and the expression of two Lotus COPT genes is induced. These results strongly suggest that the Lotus COPT proteins identified in this work function in copper uptake. In addition, the fact that environmental conditions affect the expression of certain COPT genes supports their involvement in adaptive mechanisms and envisages putative biotechnological strategies to improve cattle copper nutrition.

scholarly journals Antibacterial Prodrugs to Overcome Bacterial Resistance

Molecules ◽  
2020 ◽  
Vol 25 (7) ◽  
pp. 1543 ◽  
Author(s):  
Buthaina Jubeh ◽  
Zeinab Breijyeh ◽  
Rafik Karaman
Keyword(s):  
Bacterial Resistance ◽  
Active Drug ◽  
Resistant Bacteria ◽  
Drug Resistant ◽  
Pharmacological Effects ◽  
New Drug ◽  
Drug Resistant Bacteria ◽  
Drug Treatments ◽  
New Treatments ◽  
Novel Antibiotics

Bacterial resistance to present antibiotics is emerging at a high pace that makes the development of new treatments a must. At the same time, the development of novel antibiotics for resistant bacteria is a slow-paced process. Amid the massive need for new drug treatments to combat resistance, time and effort preserving approaches, like the prodrug approach, are most needed. Prodrugs are pharmacologically inactive entities of active drugs that undergo biotransformation before eliciting their pharmacological effects. A prodrug strategy can be used to revive drugs discarded due to a lack of appropriate pharmacokinetic and drug-like properties, or high host toxicity. A special advantage of the use of the prodrug approach in the era of bacterial resistance is targeting resistant bacteria by developing prodrugs that require bacterium-specific enzymes to release the active drug. In this article, we review the up-to-date implementation of prodrugs to develop medications that are active against drug-resistant bacteria.

scholarly journals Optimizing Bioremediation: Elucidating Copper Accumulation Mechanisms of Acinetobacter sp. IrC2 Isolated From an Industrial Waste Treatment Center

2021 ◽  
Vol 12 ◽  
Author(s):  
Wahyu Irawati ◽  
Eric Santoso Djojo ◽  
Lucia Kusumawati ◽  
Triwibowo Yuwono ◽  
Reinhard Pinontoan
Keyword(s):  
Membrane Proteins ◽  
Industrial Waste ◽  
Waste Treatment ◽  
Protein Profile ◽  
Copper Resistance ◽  
Copper Stress ◽  
Treatment Center ◽  
Resistant Bacteria ◽  
Cu Ions ◽  
Industrial Waste Treatment

Acinetobacter sp. IrC2 is a copper-resistant bacterium isolated from an industrial waste treatment center in Rungkut, Surabaya. Copper-resistant bacteria are known to accumulate copper inside the cells as a mechanism to adapt to a copper-contaminated environment. Periplasmic and membrane proteins CopA and CopB have been known to incorporate copper as a mechanism of copper resistance. In the present study, protein profile changes in Acinetobacter sp. IrC2 following exposure to copper stress were analyzed to elucidate the copper resistance mechanism. Bacteria were grown in a Luria Bertani agar medium with and without CuSO4 supplementation. Intracellular copper ion accumulation was quantified using atomic absorption spectrophotometry. Changes in protein profile were assessed using sodium dodecyl sulfate polyacrylamide gel electrophoresis. The results showed that 6 mM CuSO4 was toxic for Acinetobacter sp. IrC2, and as a response to this copper-stress condition, the lag phase was prolonged to 18 h. It was also found that the bacteria accumulated copper to a level of 508.01 mg/g of cells’ dry weight, marked by a change in colony color to green. The protein profile under copper stress was altered as evidenced by the appearance of five specific protein bands with molecular weights of 68.0, 60.5, 38.5, 24.0, and 20.5 kDa, suggesting the presence of CopA, multicopper oxidase (MCO), CopB, universal stress protein (Usp), and superoxide dismutase (SOD) and/or DNA-binding protein from starved cells, respectively. We proposed that the mechanism of bacterial resistance to copper involves CopA and CopB membrane proteins in binding Cu ions in the periplasm and excreting excess Cu ions as well as involving enzymes that play a role in the detoxification process, namely, SOD, MCO, and Usp to avoid cell damage under copper stress.

scholarly journals The multi-drug efflux system AcrABZ-TolC is essential for infection of Salmonella Typhimurium by the flagellum-dependent bacteriophage Chi

2021 ◽  
Author(s):  
Nathaniel C. Esteves ◽  
Steffen Porwollik ◽  
Michael McClelland ◽  
Birgit E. Scharf
Keyword(s):  
Salmonella Enterica ◽  
Bacterial Infections ◽  
Gene Deletion ◽  
Efflux Pump ◽  
Resistant Bacteria ◽  
Drug Efflux ◽  
Efflux System ◽  
Antibiotic Resistant ◽  
Surface Receptors ◽  
Genes Encoding

Bacteriophages are the most abundant biological entities in the biosphere. Due to their host specificity and ability to kill bacteria rapidly, bacteriophages have many potential healthcare applications, including therapy against antibiotic-resistant bacteria. Infection by flagellotropic bacteriophages requires a properly rotating bacterial flagellar filament. The flagella-dependent phage χ (Chi) infects serovars of the pathogenic enterobacterium Salmonella enterica. However, cell surface receptors and proteins involved in other stages of χ infection have not been discovered to date. We screened a multi-gene deletion library of S. enterica serovar Typhimurium by spotting mutants on soft agar plates seeded with bacteriophage χ and monitoring their ability to grow and form a swim ring, a characteristic of bacteriophage-resistant motile mutants. Those multi-gene deletion regions identified to be important for χ infectivity were further investigated by characterizing the phenotypes of corresponding single-gene deletion mutants. This way, we identified motile mutants with varying degrees of resistance to χ. Deletions in individual genes encoding the AcrABZ-TolC multi-drug efflux system drastically reduced infection by bacteriophage χ. Furthermore, an acrABtolC triple deletion strain was fully resistant to χ. Infection was severely reduced but not entirely blocked by the deletion of the gene tig encoding the molecular chaperone trigger factor. Finally, deletion in genes encoding enzymes involved in the synthesis of the antioxidants glutathione (GSH) and uric acid resulted in reduced infectivity. Our findings begin to elucidate poorly understood processes involved in later stages of flagellotropic bacteriophage infection and informs research aimed at the use of bacteriophages to combat antibiotic-resistant bacterial infections. IMPORTANCE Antimicrobial resistance is a large concern in the healthcare field. With more multi-drug resistant bacterial pathogens emerging, other techniques for eliminating bacterial infections are being explored. Among these is phage therapy, where combinations of specific phages are used to treat infections. Generally, phages utilize cell appendages and surface receptors for the initial attachment to their host. Phages that are flagellotropic are of particular interest because flagella are often important in bacterial virulence, making resistance to attachment of these phages harder to achieve without reducing virulence. This study discovered the importance of a multi-drug efflux pump for the infection of Salmonella enterica by a flagellotropic phage. In theory, if a bacterial pathogen develops phage resistance by altering expression of the efflux pump then the pathogen would simultaneously become more susceptible to the antibiotic substrates of the pump. Thus, co-administering antibiotics and flagellotropic phage may be a particularly potent antibacterial therapy.

scholarly journals Recent Progress in the Development of Small-Molecule FtsZ Inhibitors as Chemical Tools for the Development of Novel Antibiotics

Antibiotics ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 217 ◽  
Author(s):  
Laura Carro
Keyword(s):  
Small Molecule ◽  
Bacterial Infections ◽  
Public Health Problem ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Bacterial Cell Division ◽  
Promising Target ◽  
Ftsz Inhibitors ◽  
Novel Antibiotics ◽  
Urgent Action

Antibiotics are potent pharmacological weapons against bacterial pathogens, nevertheless their efficacy is becoming compromised due to the worldwide emergence and spread of multidrug-resistant bacteria or “superbugs”. Antibiotic resistance is rising to such dangerous levels that the treatment of bacterial infections is becoming a clinical challenge. Therefore, urgent action is needed to develop new generations of antibiotics that will help tackle this increasing and serious public health problem. Due to its essential role in bacterial cell division, the tubulin-like protein FtsZ has emerged as a promising target for the development of novel antibiotics with new mechanisms of action. This review highlights the medicinal chemistry efforts towards the identification of small-molecule FtsZ inhibitors with antibacterial activity in the last three years.

scholarly journals Role of the Multidrug Efflux System MexXY in the Emergence of Moderate Resistance to Aminoglycosides among Pseudomonas aeruginosa Isolates from Patients with Cystic Fibrosis

2004 ◽  
Vol 48 (5) ◽  
pp. 1676-1680 ◽  
Author(s):  
Christelle Vogne ◽  
Julio Ramos Aires ◽  
Christiane Bailly ◽  
Didier Hocquet ◽  
Patrick Plésiat
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Fold Increase ◽  
Resistant Bacteria ◽  
Multidrug Efflux ◽  
Efflux System ◽  
Active Efflux ◽  
Moderate Resistance ◽  
Moderately Resistant

ABSTRACT This study investigates the role of active efflux system MexXY in the emergence of aminoglycoside (AG) resistance among cystic fibrosis (CF) isolates of Pseudomonas aeruginosa. Three genotypically related susceptible and resistant (S/R) bacterial pairs and three other AG-resistant CF strains were compared to four non-CF strains moderately resistant to AGs. As demonstrated by immunoblot experiments, pump MexY was strongly overproduced in all of the resistant bacteria. This MexXY upregulation was associated with a 2- to 16-fold increase in the MICs of AGs in the S/R pairs and lower intracellular accumulation of dihydrostreptomycin. Alterations in mexZ, the repressor gene of operon mexXY, were found in all of the AG-resistant CF isolates and in one non-CF strain. Complementation of these bacteria with a plasmid-borne mexZ gene dramatically reduced the MICs of AGs, thus highlighting the role played by MexXY in the development of moderate resistance in CF patients. In contrast, complementation of the three non-CF strains showing wild-type mexZ genes left residual levels of resistance to AGs. These data indicate that a locus different from mexZ may be involved in overproduction of MexXY and that other nonenzymatic mechanisms contribute to AG resistance in P. aeruginosa.

scholarly journals Development of a Tightly Regulatable Copper-Mediated Gene Switch System in Dermatophytes

2012 ◽  
Vol 78 (15) ◽  
pp. 5204-5211 ◽  
Author(s):  
Atsushi Iwata ◽  
Mohamed Mahdi Alshahni ◽  
Yayoi Nishiyama ◽  
Koichi Makimura ◽  
Shigeru Abe ◽  
...  
Keyword(s):  
Drug Targets ◽  
Efflux Pump ◽  
Molecular Genetic ◽  
Genetic Research ◽  
Promoter Sequence ◽  
Essential Genes ◽  
Regulation System ◽  
Copper Transporter ◽  
Content Type ◽  
Targeted Gene Deletion

ABSTRACTTargeted gene deletion is now available for molecular genetic research of dermatophytes, and the physiological roles of several genes have been elucidated. However, this method cannot be applied to essential genes, which can be potential drug targets. To overcome this limitation, we have developed a conditional gene knockdown system using a copper-responsive promoter. The promoter sequence of the copper transporter geneCTR4(PCTR4) and that of the copper efflux pump geneCRP1(PCRP1) derived fromTrichophyton rubrumwere examined for their response to copper inArthroderma vanbreuseghemii. PCTR4was demonstrated to repress expression of a reporter gene in the presence of copper, while the activity of PCRP1was induced by addition of copper. Importantly, PCTR4regulated the gene expression more tightly. Furthermore, when PCTR4was applied to regulate the expression of the endogenous genesERG1andTRP5, their conditional mutants exhibited decreased growth activity under the repressive conditions. These results suggest that the PCTR4-based gene regulation system represents a powerful tool for identification and characterization of a broad range of genes, including essential genes, in dermatophytes.

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