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1.
An Overview of Ozone Therapy for Treating Foot Ulcers in Patients With Diabetes.
Wen, Q, Chen, Q
The American journal of the medical sciences. 2020;(2):112-119
Abstract
Diabetic foot ulcer (DFU) is one of the most common and severe complications of diabetes mellitus, which is becoming increasingly prevalent throughout the world, with high mortality and morbidity. Because of the complex pathophysiological processes involved, DFU is difficult to treat effectively with traditional therapies. Ozone therapy, an emerging method, has been reported as potentially beneficial for closure of DFUs and may gradually move to the forefront of clinical practice. Possible mechanisms of action include antioxidant capacity, pathogen inactivation, vascular and endogenous growth factor modulation, and immune system activation. However, some researchers are skeptical about its safety, and clinical trials are lacking. This article reviews the current research and application of ozone therapy for DFUs.
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2.
Alterocin, an Antibiofilm Protein Secreted by Pseudoalteromonas sp. Strain 3J6.
Jouault, A, Gobet, A, Simon, M, Portier, E, Perennou, M, Corre, E, Gaillard, F, Vallenet, D, Michel, G, Fleury, Y, et al
Applied and environmental microbiology. 2020;(20)
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Abstract
We sought to identify and study the antibiofilm protein secreted by the marine bacterium Pseudoalteromonas sp. strain 3J6. The latter is active against marine and terrestrial bacteria, including Pseudomonas aeruginosa clinical strains forming different biofilm types. Several amino acid sequences were obtained from the partially purified antibiofilm protein, named alterocin. The Pseudoalteromonas sp. 3J6 genome was sequenced, and a candidate alt gene was identified by comparing the genome-encoded proteins to the sequences from purified alterocin. Expressing the alt gene in another nonactive Pseudoalteromonas sp. strain, 3J3, demonstrated that it is responsible for the antibiofilm activity. Alterocin is a 139-residue protein that includes a predicted 20-residue signal sequence, which would be cleaved off upon export by the general secretion system. No sequence homology was found between alterocin and proteins of known functions. The alt gene is not part of an operon and adjacent genes do not seem related to alterocin production, immunity, or regulation, suggesting that these functions are not fulfilled by devoted proteins. During growth in liquid medium, the alt mRNA level peaked during the stationary phase. A single promoter was experimentally identified, and several inverted repeats could be binding sites for regulators. alt genes were found in about 30% of the Pseudoalteromonas genomes and in only a few instances of other marine bacteria of the Hahella and Paraglaciecola genera. Comparative genomics yielded the hypothesis that alt gene losses occurred within the Pseudoalteromonas genus. Overall, alterocin is a novel kind of antibiofilm protein of ecological and biotechnological interest.IMPORTANCE Biofilms are microbial communities that develop on solid surfaces or interfaces and are detrimental in a number of fields, including for example food industry, aquaculture, and medicine. In the latter, antibiotics are insufficient to clear biofilm infections, leading to chronic infections such as in the case of infection by Pseudomonas aeruginosa of the lungs of cystic fibrosis patients. Antibiofilm molecules are thus urgently needed to be used in conjunction with conventional antibiotics, as well as in other fields of application, especially if they are environmentally friendly molecules. Here, we describe alterocin, a novel antibiofilm protein secreted by a marine bacterium belonging to the Pseudoalteromonas genus, and its gene. Alterocin homologs were found in about 30% of Pseudoalteromonas strains, indicating that this new family of antibiofilm proteins likely plays an important albeit nonessential function in the biology of these bacteria. This study opens up the possibility of a variety of applications.
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3.
Understanding the impact of antibiotic perturbation on the human microbiome.
Schwartz, DJ, Langdon, AE, Dantas, G
Genome medicine. 2020;(1):82
Abstract
The human gut microbiome is a dynamic collection of bacteria, archaea, fungi, and viruses that performs essential functions for immune development, pathogen colonization resistance, and food metabolism. Perturbation of the gut microbiome's ecological balance, commonly by antibiotics, can cause and exacerbate diseases. To predict and successfully rescue such perturbations, first, we must understand the underlying taxonomic and functional dynamics of the microbiome as it changes throughout infancy, childhood, and adulthood. We offer an overview of the healthy gut bacterial architecture over these life stages and comment on vulnerability to short and long courses of antibiotics. Second, the resilience of the microbiome after antibiotic perturbation depends on key characteristics, such as the nature, timing, duration, and spectrum of a course of antibiotics, as well as microbiome modulatory factors such as age, travel, underlying illness, antibiotic resistance pattern, and diet. In this review, we discuss acute and chronic antibiotic perturbations to the microbiome and resistome in the context of microbiome stability and dynamics. We specifically discuss key taxonomic and resistance gene changes that accompany antibiotic treatment of neonates, children, and adults. Restoration of a healthy gut microbial ecosystem after routine antibiotics will require rationally managed exposure to specific antibiotics and microbes. To that end, we review the use of fecal microbiota transplantation and probiotics to direct recolonization of the gut ecosystem. We conclude with our perspectives on how best to assess, predict, and aid recovery of the microbiome after antibiotic perturbation.
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4.
Molecular Structure and Functional Analysis of Pyocin S8 from Pseudomonas aeruginosa Reveals the Essential Requirement of a Glutamate Residue in the H-N-H Motif for DNase Activity.
Turano, H, Gomes, F, Domingos, RM, Degenhardt, MFS, Oliveira, CLP, Garratt, RC, Lincopan, N, Netto, LES
Journal of bacteriology. 2020;(21)
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Abstract
Multidrug resistance (MDR) is a serious threat to public health, making the development of new antimicrobials an urgent necessity. Pyocins are protein antibiotics produced by Pseudomonas aeruginosa strains to kill closely related cells during intraspecific competition. Here, we report an in-depth biochemical, microbicidal, and structural characterization of a new S-type pyocin, named S8. Initially, we described the domain organization and secondary structure of S8. Subsequently, we observed that a recombinant S8 composed of the killing subunit in complex with the immunity (ImS8) protein killed the strain PAO1. Furthermore, mutation of a highly conserved glutamic acid to alanine (Glu100Ala) completely inhibited this antimicrobial activity. The integrity of the H-N-H motif is probably essential in the killing activity of S8, as Glu100 is a highly conserved residue of this motif. Next, we observed that S8 is a metal-dependent endonuclease, as EDTA treatment abolished its ability to cleave supercoiled pUC18 plasmid. Supplementation of apo S8 with Ni2+ strongly induced this DNase activity, whereas Mn2+ and Mg2+ exhibited moderate effects and Zn2+ was inhibitory. Additionally, S8 bound Zn2+ with a higher affinity than Ni2+ and the Glu100Ala mutation decreased the affinity of S8 for these metals, as shown by isothermal titration calorimetry (ITC). Finally, we describe the crystal structure of the Glu100Ala S8 DNase-ImS8 complex at 1.38 Å, which gave us new insights into the endonuclease activity of S8. Our results reinforce the possibility of using pyocin S8 as an alternative therapy for infections caused by MDR strains, while leaving commensal human microbiota intact.IMPORTANCE Pyocins are proteins produced by Pseudomonas aeruginosa strains that participate in intraspecific competition and host-pathogen interactions. They were first described in the 1950s and since then have gained attention as possible new antibiotics. However, there is still only scarce information about the molecular mechanisms by which these molecules induce cell death. Here, we show that the metal-dependent endonuclease activity of pyocin S8 is involved with its antimicrobial action against strain PAO1. We also describe that this killing activity is dependent on a conserved Glu residue within the H-N-H motif. The potency and selectivity of pyocin S8 toward a narrow spectrum of P. aeruginosa strains make this protein an attractive antimicrobial alternative for combatting MDR strains, while leaving commensal human microbiota intact.
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Iron Metabolism at the Interface between Host and Pathogen: From Nutritional Immunity to Antibacterial Development.
Marchetti, M, De Bei, O, Bettati, S, Campanini, B, Kovachka, S, Gianquinto, E, Spyrakis, F, Ronda, L
International journal of molecular sciences. 2020;(6)
Abstract
Nutritional immunity is a form of innate immunity widespread in both vertebrates and invertebrates. The term refers to a rich repertoire of mechanisms set up by the host to inhibit bacterial proliferation by sequestering trace minerals (mainly iron, but also zinc and manganese). This strategy, selected by evolution, represents an effective front-line defense against pathogens and has thus inspired the exploitation of iron restriction in the development of innovative antimicrobials or enhancers of antimicrobial therapy. This review focuses on the mechanisms of nutritional immunity, the strategies adopted by opportunistic human pathogen Staphylococcus aureus to circumvent it, and the impact of deletion mutants on the fitness, infectivity, and persistence inside the host. This information finally converges in an overview of the current development of inhibitors targeting the different stages of iron uptake, an as-yet unexploited target in the field of antistaphylococcal drug discovery.
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Therapeutic Value of Vitamin D as an Adjuvant Therapy in Neonates with Sepsis.
Hagag, AA, El Frargy, MS, Houdeeb, HA
Infectious disorders drug targets. 2020;(4):440-447
Abstract
UNLABELLED Sepsis is unusual systemic reaction to an ordinary infection, and it probably represents a pattern of response by the immune system to the injury. Vitamin D is a fat-soluble steroid hormone that contributes to the maintenance of normal calcium homeostasis and skeletal mineralization. Vitamin D has an important role in the regulation of both innate and adaptive immune systems. AIM OF THE WORK The current study aimed to evaluate the therapeutic value of vitamin D supplementation as an adjuvant therapy in neonates with sepsis. SUBJECTS AND METHOD This study included 60 neonates with sepsis who were randomly divided into 2 equal groups; group I: 30 neonates with sepsis who received antibiotic only, Group II: 30 neonates with sepsis who received antibiotic therapy and vitamin D. This study also included 30 healthy neonates as a control group. For all patients and controls, serum level of 25 (OH) vitamin D and highly sensitive C reactive protein (hs-CRP) were immunoassayed. RESULTS There is no significant difference between groups I, II and controls regarding weight, gestational age, sex and mode of delivery. There were significant differences between groups I and II in sepsis score and hs-CRP after 3, 7, 10 days of treatment (p values for sepsis score were 0.009, 0.006, 0.004 respectively and for hs-CRP were 0.015, 0.001, 0.001 respectively). There was a significant difference in immature /total (I/T) ratio after 7, and 10 days of treatment (p value= 0.045, 0.025, respectively,) while there was no significant difference in immature /total (I/T) ratio after 3 days of treatment (p value = 0.624).Serum 25(OH) vitamin D levels were significantly lower in neonates with sepsis (group I and II) than the controls (p value < 0.05, while there were no significant differences between the three groups considering serum calcium and phosphorus levels (P =1.000, 1.000, respectively). Isolated organisms from blood culture in neonates with sepsis (group I and group II) were most commonly B- hemolytic streptococci, E-coli, hemophilus influenza and staphylococcus aurous. There was a significant negative correlation between hs-CRP and serum 25 (OH) vitamin in group II on entry (r = - 0.832 and P value = 0.001) and after 2 weeks (r = - 0.590 and P value = 0.021). ROC curve of specificity and sensitivity of 25 (OH) vitamin D level in prediction of early-onset neonatal sepsis showed that cutoff value of vitamin D was ≤20 ng/ml, sensitivity was 100%, specificity was 73%, positive predictive value was 73%, negative predictive value was 100% and accuracy was 87. CONCLUSION AND RECOMMENDATION Serum 25 (OH) vitamin D levels of neonates with the early onset neonatal sepsis were significantly lower than the healthy controls. Vitamin D supplementation improved sepsis score and decrease high levels of hs-CRP; this reflects the role of vitamin D as a target therapy for neonatal sepsis. Further studies are warranted to confirm the therapeutic value of vitamin D in neonatal sepsis.
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7.
Antibiotic adjuvant therapy for pulmonary infection in cystic fibrosis.
Hurley, MN, Smith, S, Forrester, DL, Smyth, AR
The Cochrane database of systematic reviews. 2020;(7):CD008037
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Abstract
BACKGROUND Cystic fibrosis is a multi-system disease characterised by the production of thick secretions causing recurrent pulmonary infection, often with unusual bacteria. This leads to lung destruction and eventually death through respiratory failure. There are no antibiotics in development that exert a new mode of action and many of the current antibiotics are ineffective in eradicating the bacteria once chronic infection is established. Antibiotic adjuvants - therapies that act by rendering the organism more susceptible to attack by antibiotics or the host immune system, by rendering it less virulent or killing it by other means, would be a significant therapeutic advance. This is an update of a previously published review. OBJECTIVES To determine if antibiotic adjuvants improve clinical and microbiological outcome of pulmonary infection in people with cystic fibrosis. SEARCH METHODS We searched the Cystic Fibrosis Trials Register which is compiled from database searches, hand searches of appropriate journals and conference proceedings. Date of most recent search: 16 January 2020. We also searched MEDLINE (all years) on 14 February 2019 and ongoing trials registers on 06 April 2020. SELECTION CRITERIA Randomised controlled trials and quasi-randomised controlled trials of a therapy exerting an antibiotic adjuvant mechanism of action compared to placebo or no therapy for people with cystic fibrosis. DATA COLLECTION AND ANALYSIS Two of the authors independently assessed and extracted data from identified trials. MAIN RESULTS We identified 42 trials of which eight (350 participants) that examined antibiotic adjuvant therapies are included. Two further trials are ongoing and five are awaiting classification. The included trials assessed β-carotene (one trial, 24 participants), garlic (one trial, 34 participants), KB001-A (a monoclonal antibody) (two trials, 196 participants), nitric oxide (two trials, 30 participants) and zinc supplementation (two trials, 66 participants). The zinc trials recruited children only, whereas the remaining trials recruited both adults and children. Three trials were located in Europe, one in Asia and four in the USA. Three of the interventions measured our primary outcome of pulmonary exacerbations (β-carotene, mean difference (MD) -8.00 (95% confidence interval (CI) -18.78 to 2.78); KB001-A, risk ratio (RR) 0.25 (95% CI 0.03 to 2.40); zinc supplementation, RR 1.85 (95% CI 0.65 to 5.26). β-carotene and KB001-A may make little or no difference to the number of exacerbations experienced (low-quality evidence); whereas, given the moderate-quality evidence we found that zinc probably makes no difference to this outcome. Respiratory function was measured in all of the included trials. β-carotene and nitric oxide may make little or no difference to forced expiratory volume in one second (FEV1) (low-quality evidence), whilst garlic probably makes little or no difference to FEV1 (moderate-quality evidence). It is uncertain whether zinc or KB001-A improve FEV1 as the certainty of this evidence is very low. Few adverse events were seen across all of the different interventions and the adverse events that were reported were mild or not treatment-related (quality of the evidence ranged from very low to moderate). One of the trials (169 participants) comparing KB001-A and placebo, reported on the time to the next course of antibiotics; results showed there is probably no difference between groups, HR 1.00 (95% CI 0.69 to 1.45) (moderate-quality evidence). Quality of life was only reported in the two KB001-A trials, which demonstrated that there may be little or no difference between KB001-A and placebo (low-quality evidence). Sputum microbiology was measured and reported for the trials of KB001-A and nitric oxide (four trials). There was very low-quality evidence of a numerical reduction in Pseudomonas aeruginosa density with KB001-A, but it was not significant. The two trials looking at the effects of nitric oxide reported significant reductions in Staphylococcus aureus and near-significant reductions in Pseudomonas aeruginosa, but the quality of this evidence is again very low. AUTHORS' CONCLUSIONS We could not identify an antibiotic adjuvant therapy that we could recommend for treating of lung infection in people with cystic fibrosis. The emergence of increasingly resistant bacteria makes the reliance on antibiotics alone challenging for cystic fibrosis teams. There is a need to explore alternative strategies, such as the use of adjuvant therapies. Further research is required to provide future therapeutic options.
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Review of Anti-Bacterial Activities of Curcumin against Pseudomonas aeruginosa.
Neyestani, Z, Ebrahimi, SA, Ghazaghi, A, Jalili, A, Sahebkar, A, Rahimi, HR
Critical reviews in eukaryotic gene expression. 2019;(5):377-385
Abstract
The prevention and pharmacotherapy of infectious diseases are of great importance. Among others, infections caused by Pseudomonas aeruginosa have a high mortality rate. This bacterium is the third most common cause of nosocomial infections, and characteristics such as multiple virulence factors, ability to survive, environmental spread, and resistance to antibiotics have made it a potential pathogen, especially for people with compromised immune systems. Considering bacterial resistance to current medications, high cost, and side effects, the need to provide new and effective therapies is highlighted. Curcumin is a dietary polyphenolic compound that has a wide range of therapeutic properties, including antibacterial effects. It has been the subject of increasing research exploring its potential utility in infectious diseases. In this review, the antibacterial effects of curcumin against Pseudomonas aeruginosa are discussed.
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Antimicrobial Peptides: the Achilles' Heel of Antibiotic Resistance?
Lewies, A, Du Plessis, LH, Wentzel, JF
Probiotics and antimicrobial proteins. 2019;(2):370-381
Abstract
Antibiotic resistance is an imminent threat to the effective treatment of bacterial infections, and alternative antibiotic strategies are urgently required. The golden epoch of antibiotics is coming to an end, and the development of new therapeutic agents to combat bacterial infections should be prioritized. This article will review the potential of antimicrobial peptides (AMPs) to combat the threat of antimicrobial resistance. The modern-day antimicrobial resistance dilemma is briefly discussed followed by a review of the potential of AMPs to be used alone or in combination with current antibiotics in order to enhance antibacterial properties of antibiotics while also potentially combatting resistance. This article reiterates that many AMPs exhibit direct microbial killing activity and also play an integral role in the innate immune system. These properties make AMPs attractive alternative antimicrobial agents. Furthermore, AMPs are promising candidates to be used as adjuvants in combination with current antibiotics in order to combat antibiotic resistance. Combinations of AMPs and antibiotics are less likely to develop resistance or transmit cross-resistance. The further identification and therapeutic development of AMPs and antibiotic-AMP combinations are strongly recommended.
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An Innovative Technique in Local Antibiotic Delivery Method in Open Infected Wounds of the Musculoskeletal System.
Shekhar, C
The international journal of lower extremity wounds. 2019;(2):153-160
Abstract
Bone and soft tissue infections are difficult problems in orthopedic surgery. Infections resulting in chronic osteomyelitis if established are difficult to eradicate. The delivery of local antibiotics for the treatment of open infected wounds of the musculo skeletal system is a more logical approach to treat these infections. Antibiotics given systemically are unable to achieve minimum inhibitory concentration in areas of infected wounds which are ischemic or relatively avascular. And also these antibiotics given over a prolonged period lead to significant toxicity and side effects and emergence of resistant bacteria. The author has been treating difficult cases of infected wounds sustained in road accidents, wounds (diabetic ulcers) in Diabetes Mellitus with necrotizing fasciitis and post operative infections with discharging sinuses with infected implants inside by his own innovative method of antibiotic delivery. The infected open wounds have been treated by application of Vitamin D3 granules impregnated with Tobramycin or Tobramycin and Vancomycin combined. All the patients responded successfully to this novel method of treatment which is extremely simple, effective, low cost, without any complications or side effects and has shown excellent results. Not only the Vitamin D3 granules act as a carrier of the antibiotic locally but also have properties of boosting immunity, and promote tissue healing. It also produces an antibiotic like substance Cathelicidin which kills bacteria and promotes growth of the bone and restores the bone mineral density.