Potential Application of Combined Therapy with Lectins as a Therapeutic Strategy for the Treatment of Bacterial Infections
02 May 2021-The Journal of Antibiotics (Multidisciplinary Digital Publishing Institute)-Vol. 10, Iss: 5, pp 520
TL;DR: In this paper, a review provides an update on the experimental application of antibiotic therapies based on the synergic combination with lectins to treat infections specifically caused by multidrug-resistant and biofilm-producing Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa.
Abstract: Antibiotic monotherapy may become obsolete mainly due to the continuous emergence of resistance to available antimicrobials, which represents a major uncertainty to human health. Taking into account that natural products have been an inexhaustible source of new compounds with clinical application, lectins are certainly one of the most versatile groups of proteins used in biological processes, emerging as a promising alternative for therapy. The ability of lectins to recognize carbohydrates present on the cell surface allowed for the discovery of a wide range of activities. Currently the number of antimicrobials in research and development does not match the rate at which resistance mechanisms emerge to an effective antibiotic monotherapy. A promising therapeutic alternative is the combined therapy of antibiotics with lectins to enhance its spectrum of action, minimize adverse effects, and reduce resistance to treatments. Thus, this review provides an update on the experimental application of antibiotic therapies based on the synergic combination with lectins to treat infections specifically caused by multidrug-resistant and biofilm-producing Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. We also briefly discuss current strategies involving the modulation of the gut microbiota, its implications for antimicrobial resistance, and highlight the potential of lectins to modulate the host immune response against oxidative stress.
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TL;DR: The observed efficacy of this non-cytotoxic therapeutic combination (AD-L@Ag(0)) was found to be better than that reported in the existing literature for treating extremely drug-resistant bacterial strains, as well as for reducing the bacterial infection load at a surgical site in a small animal BALB/c model.
Abstract: Bacteria organized in biofilms show significant tolerance to conventional antibiotics compared to their planktonic counterparts and form the basis for chronic infections. Biofilms are composites of different types of extracellular polymeric substances that help in resisting several host-defense measures, including phagocytosis. These are increasingly being recognized as a passive virulence factor that enables many infectious diseases to proliferate and an essential contributing facet to anti-microbial resistance. Thus, inhibition and dispersion of biofilms are linked to addressing the issues associated with therapeutic challenges imposed by biofilms. This report is to address this complex issue using a self-assembled guanidinium–Ag(0) nanoparticle (AD-L@Ag(0)) hybrid gel composite for executing a combination therapy strategy for six difficult to treat biofilm-forming and multidrug-resistant bacteria. Improved efficacy was achieved primarily through effective biofilm inhibition and dispersion by the cationic guanidinium ion derivative, while Ag(0) contributes to the subsequent bactericidal activity on planktonic bacteria. Minimum Inhibitory Concentration (MIC) of the AD-L@Ag(0) formulation was tested against Acinetobacter baumannii (25 μg mL−1), Pseudomonas aeruginosa (0.78 μg mL−1), Staphylococcus aureus (0.19 μg mL−1), Klebsiella pneumoniae (0.78 μg mL−1), Escherichia coli (clinical isolate (6.25 μg mL−1)), Klebsiella pneumoniae (clinical isolate (50 μg mL−1)), Shigella flexneri (clinical isolate (0.39 μg mL−1)) and Streptococcus pneumoniae (6.25 μg mL−1). Minimum bactericidal concentration, and MBIC50 and MBIC90 (Minimum Biofilm Inhibitory Concentration at 50% and 90% reduction, respectively) were evaluated for these pathogens. All these results confirmed the efficacy of the formulation AD-L@Ag(0). Minimum Biofilm Eradication Concentration (MBEC) for the respective pathogens was examined by following the exopolysaccharide quantification method to establish its potency in inhibition of biofilm formation, as well as eradication of mature biofilms. These effects were attributed to the bactericidal effect of AD-L@Ag(0) on biofilm mass-associated bacteria. The observed efficacy of this non-cytotoxic therapeutic combination (AD-L@Ag(0)) was found to be better than that reported in the existing literature for treating extremely drug-resistant bacterial strains, as well as for reducing the bacterial infection load at a surgical site in a small animal BALB/c model. Thus, AD-L@Ag(0) could be a promising candidate for anti-microbial coatings on surgical instruments, wound dressing, tissue engineering, and medical implants.
7 citations
TL;DR: Melittin alone was effective against MDR-MRSE isolates and this antimicrobial peptide showed highly synergistic effects with vancomycin and rifampin without causing toxicity, suggesting the combination of melittin and traditional antibiotics could be a promising strategy for the treatment of infections caused by MDR -MRSE.
Abstract: Methicillin-resistant Staphylococcus epidermidis (MRSE) strains are increasingly emerging as serious pathogens because they can be resistant to many antibiotics called multidrug resistance (MDR) that limit the therapeutic options. In the case of vancomycin- and rifampin-resistant MDR-MRSE, the physicians are not allowed to increase the doses of antibiotics because of severe toxicity. Accordingly, we investigated the synergistic activity of melittin antimicrobial peptide with vancomycin and rifampin against vancomycin-resistant, and rifampin-resistant MDR-MRSE isolates. Minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), fractional inhibitory concentration index (FICi), and fractional bactericidal concentration index (FBCi) of antimicrobial agents against isolates were determined. Coagulate activities and serum and salt stability as well as melittin cytotoxicity on the human embryonic kidney (HEK) 293 cells and human red blood cells (RBCs) at their synergistic concentrations. MIC and MBC values for melittin were in the range of 0.312–2.5 and 0.312–5, respectively. Results also showed that the interaction of melittin with drugs was highly synergistic in which the geometric means of FICi and FBCi were < 0.5. Induced synergism led to a decrease in melittin, rifampin, and vancomycin concentrations by 8–1,020, 2–16, and 4–16-folds, respectively. This phenomenon caused a reduction in melittin toxicity by which the synergistic concentration of melittin needed to kill bacteria did not show cytotoxicity and hemolytic activity. Besides, no coagulation activity was found for the synergistic and alone concentrations of melittin in both Prothrombin Time (PT) and Partial Thromboplastin Time (PTT). Interestingly, the antibacterial activity of melittin in Mueller Hinton Broth (MHB) containing human serum did no significant differences between MIC and MBC values of melittin in MHB and MHB containing 10% human serum. The present findings showed that the therapeutic index of melittin was improved by 32.08- and 12.82-folds when combined with vancomycin and rifampin, respectively. Taken together, the obtained data show that melittin alone was effective against MDR-MRSE isolates and this antimicrobial peptide showed highly synergistic effects with vancomycin and rifampin without causing toxicity. Therefore, the combination of melittin and traditional antibiotics could be a promising strategy for the treatment of infections caused by MDR-MRSE.
5 citations
12 May 2023
TL;DR: In this article , an iron complex (Fe16) was synthesized and characterized using spectroscopy methods, and it was tested in combination with ampicillin against Staphylococcus aureus.
Abstract: Abstract Objectives Resistance to antibiotics among bacteria of clinical importance, including Staphylococcus aureus , is a serious problem worldwide and the search for alternatives is needed. Some metal complexes have antibacterial properties and when combined with antibiotics, they may increase bacterial sensitivity to antimicrobials. In this study, we synthesized the iron complex and tested it in combination with ampicillin (Fe16 + AMP) against S. aureus . Methods An iron complex (Fe16) was synthesized and characterized using spectroscopy methods. Confirmation of the synergistic effect between the iron complex (Fe16) and ampicillin (AMP) was performed using ζ – potential, infrared spectra and FICI index calculated from minimum inhibitory concentration (MIC). Cytotoxic properties of combination Fe16 + AMP was evaluated on eukaryotic cell line. Impact of combination Fe16 + AMP on chosen genes of S. aureus were performed by Quantitative Real-Time PCR. Results The MIC of Fe16 + AMP was significantly lower than that of AMP and Fe16 alone. Furthermore, the infrared spectroscopy revealed the change in the ζ – potential of Fe16 + AMP. We demonstrated the ability of Fe16 + AMP to disrupt the bacterial membrane of S. aureus and that likely allowed for better absorption of AMP. In addition, the change in gene expression of bacterial efflux pumps at the sub-inhibitory concentration of AMP suggests an insufficient import of iron into the bacterial cell. At the same time, Fe16 + AMP did not have any cytotoxic effects on keratinocytes. Conclusions Combined Fe16 + AMP therapy demonstrated significant synergistic and antimicrobial effects against S. aureus . This study supports the potential of combination therapy and further research.
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TL;DR: A review of antibiotic resistance development over the past half-century can be found in this article, with the oft-restated conclusion that it is time to act and to restore the therapeutic applications of antibiotics.
Abstract: Antibiotics have always been considered one of the wonder discoveries of the 20th century. This is true, but the real wonder is the rise of antibiotic resistance in hospitals, communities, and the environment concomitant with their use. The extraordinary genetic capacities of microbes have benefitted from man's overuse of antibiotics to exploit every source of resistance genes and every means of horizontal gene transmission to develop multiple mechanisms of resistance for each and every antibiotic introduced into practice clinically, agriculturally, or otherwise. This review presents the salient aspects of antibiotic resistance development over the past half-century, with the oft-restated conclusion that it is time to act. To achieve complete restitution of therapeutic applications of antibiotics, there is a need for more information on the role of environmental microbiomes in the rise of antibiotic resistance. In particular, creative approaches to the discovery of novel antibiotics and their expedited and controlled introduction to therapy are obligatory.
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TL;DR: Owing to the heterogeneous nature of the biofilm, it is likely that there are multiple resistance mechanisms at work within a single community.
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Journal Article•
TL;DR: Decades after the first patients were treated with antibiotics, bacterial infections have again become a threat because of the rapid emergence of resistant bacteria-a crisis attributed to abuse of these medications and a lack of new drug development.
Abstract: Decades after the first patients were treated with antibiotics, bacterial infections have again become a threat because of the rapid emergence of resistant bacteria-a crisis attributed to abuse of these medications and a lack of new drug development.
3,147 citations
TL;DR: The infusion of donor feces was significantly more effective for the treatment of recurrent C. difficile infection than the use of vancomycin and patients showed increased fecal bacterial diversity, similar to that in healthy donors, with an increase in Bacteroidetes species and clostridium clusters IV and XIVa and a decrease in Proteobacteria species.
Abstract: A b s t r ac t Results The study was stopped after an interim analysis. Of 16 patients in the infusion group, 13 (81%) had resolution of C. difficile-associated diarrhea after the first infu - sion. The 3 remaining patients received a second infusion with feces from a differ- ent donor, with resolution in 2 patients. Resolution of C. difficile infection occurred in 4 of 13 patients (31%) receiving vancomycin alone and in 3 of 13 patients (23%) receiving vancomycin with bowel lavage (P<0.001 for both comparisons with the infusion group). No significant differences in adverse events among the three study groups were observed except for mild diarrhea and abdominal cramping in the in- fusion group on the infusion day. After donor-feces infusion, patients showed in- creased fecal bacterial diversity, similar to that in healthy donors, with an increase in Bacteroidetes species and clostridium clusters IV and XIVa and a decrease in Proteobacteria species. Conclusions The infusion of donor feces was significantly more effective for the treatment of recurrent C. difficile infection than the use of vancomycin. (Funded by the Nether- lands Organization for Health Research and Development and the Netherlands Organization for Scientific Research; Netherlands Trial Register number, NTR1177.)
3,081 citations
TL;DR: More human studies are now needed on SCFAs, especially, given the diverse nature of carbohydrate substrates and the SCFA patterns resulting from their fermentation, which will be key to the success of dietary recommendations to maximize colonic disease prevention.
Abstract: Interest has been recently rekindled in short chain fatty acids (SCFAs) with the emergence of prebiotics and probiotics aimed at improving colonic and systemic health Dietary carbohydrates, specifically resistant starches and dietary fiber, are substrates for fermentation that produce SCFAs, primarily acetate, propionate, and butyrate, as end products The rate and amount of SCFA production depends on the species and amounts of microflora present in the colon, the substrate source and gut transit time SCFAs are readily absorbed Butyrate is the major energy source for colonocytes Propionate is largely taken up by the liver Acetate enters the peripheral circulation to be metabolized by peripheral tissues Specific SCFA may reduce the risk of developing gastrointestinal disorders, cancer, and cardiovascular disease Acetate is the principal SCFA in the colon, and after absorption it has been shown to increase cholesterol synthesis However, propionate, a gluconeogenerator, has been shown to inhibit cholesterol synthesis Therefore, substrates that can decrease the acetate: propionate ratio may reduce serum lipids and possibly cardiovascular disease risk Butyrate has been studied for its role in nourishing the colonic mucosa and in the prevention of cancer of the colon, by promoting cell differentiation, cell-cycle arrest and apoptosis of transformed colonocytes; inhibiting the enzyme histone deacetylase and decreasing the transformation of primary to secondary bile acids as a result of colonic acidification Therefore, a greater increase in SCFA production and potentially a greater delivery of SCFA, specifically butyrate, to the distal colon may result in a protective effect Butyrate irrigation (enema) has also been suggested in the treatment of colitis More human studies are now needed, especially, given the diverse nature of carbohydrate substrates and the SCFA patterns resulting from their fermentation Short-term and long-term human studies are particularly required on SCFAs in relation to markers of cancer risk These studies will be key to the success of dietary recommendations to maximize colonic disease prevention
2,314 citations