Targeting Bacterial Antioxidant Systems for Antibiotics Development

2020 ◽  
Vol 27 (12) ◽  
pp. 1922-1939 ◽  
Author(s):  
Xiaoyuan Ren ◽  
Lili Zou ◽  
Arne Holmgren
Keyword(s):  
Defense Mechanism ◽  
Thioredoxin Reductase ◽  
Drug Repurposing ◽  
Multidrug Resistant ◽  
Modern Medicine ◽  
Resistant Bacteria ◽  
Antioxidant Systems ◽  
Gram Negative Bacteria ◽  
Reductase Inhibitors ◽  
Bacterial Cell Death

: The emergence of multidrug-resistant bacteria has become an urgent issue in modern medicine which requires novel strategies to develop antibiotics. Recent studies have supported the hypothesis that antibiotic-induced bacterial cell death is mediated by Reactive Oxygen Species (ROS). The hypothesis also highlighted the importance of antioxidant systems, the defense mechanism which contributes to antibiotic resistance. Thioredoxin and glutathione systems are the two major thiol-dependent systems which not only provide antioxidant capacity but also participate in various biological events in bacteria, such as DNA synthesis and protein folding. The biological importance makes them promising targets for novel antibiotics development. Based on the idea, ebselen and auranofin, two bacterial thioredoxin reductase inhibitors, have been found to inhibit the growth of bacteria lacking the GSH efficiently. A recent study combining ebselen and silver exhibited a strong synergistic effect against Multidrug-Resistant (MDR) Gram-negative bacteria which possess both thioredoxin and glutathione systems. These drug-repurposing studies are promising for quick clinical usage due to their well-known profile.

scholarly journals A small-molecule inhibitor of BamA impervious to efflux and the outer membrane permeability barrier

2019 ◽  
Vol 116 (43) ◽  
pp. 21748-21757 ◽  
Author(s):  
Elizabeth M. Hart ◽  
Angela M. Mitchell ◽  
Anna Konovalova ◽  
Marcin Grabowicz ◽  
Jessica Sheng ◽  
...  
Keyword(s):  
Outer Membrane ◽  
Small Molecule ◽  
Cytoplasmic Membrane ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Permeability Barrier ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Bam Complex ◽  
Induced Aggregation

The development of new antimicrobial drugs is a priority to combat the increasing spread of multidrug-resistant bacteria. This development is especially problematic in gram-negative bacteria due to the outer membrane (OM) permeability barrier and multidrug efflux pumps. Therefore, we screened for compounds that target essential, nonredundant, surface-exposed processes in gram-negative bacteria. We identified a compound, MRL-494, that inhibits assembly of OM proteins (OMPs) by the β-barrel assembly machine (BAM complex). The BAM complex contains one essential surface-exposed protein, BamA. We constructed a bamA mutagenesis library, screened for resistance to MRL-494, and identified the mutation bamAE470K. BamAE470K restores OMP biogenesis in the presence of MRL-494. The mutant protein has both altered conformation and activity, suggesting it could either inhibit MRL-494 binding or allow BamA to function in the presence of MRL-494. By cellular thermal shift assay (CETSA), we determined that MRL-494 stabilizes BamA and BamAE470K from thermally induced aggregation, indicating direct or proximal binding to both BamA and BamAE470K. Thus, it is the altered activity of BamAE470K responsible for resistance to MRL-494. Strikingly, MRL-494 possesses a second mechanism of action that kills gram-positive organisms. In microbes lacking an OM, MRL-494 lethally disrupts the cytoplasmic membrane. We suggest that the compound cannot disrupt the cytoplasmic membrane of gram-negative bacteria because it cannot penetrate the OM. Instead, MRL-494 inhibits OMP biogenesis from outside the OM by targeting BamA. The identification of a small molecule that inhibits OMP biogenesis at the cell surface represents a distinct class of antibacterial agents.

scholarly journals Isolation of Multidrug Resistant Bacteria from Aspirates of Cancer Patients

2019 ◽  
Vol 35 (1) ◽  
pp. 61-66
Author(s):  
Sunjukta Ahsan ◽  
Rayhan Mahmud ◽  
Kajal Ahsan ◽  
Shamima Begum
Keyword(s):  
Cancer Patients ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Gram Negative Bacteria ◽  
Drug Resistant ◽  
Multidrug Resistant Bacteria ◽  
Esbl Producer ◽  
Drug Resistant Bacteria ◽  
Treatment Facilities ◽  
Isolated Species

Infections due to Gram-negative bacteria are common affairs in cancer patients during aggressive therapy. The present study characterizedmulti-drug resistant bacteria (MDR) isolated from cancer aspirates collected from patients admitted to the National Cancer Hospital in Dhaka, Bangladesh. A total of 210 aspirate samples were collected from cancer patients. Out of 210 samples Acinetobacter spp.led the list of isolates (8.89%, n=45). Of these species, 50% exhibited resistance to Amoxycillin and Nitrofurantoin, each, 25% exhibited resistant to Cefotaxime, Azithromycin, Ciprofloxacin, Clindamycin, and Sulfamethoxazole. A total of 33.33% of the Bordetella spp.which accounted 6.67%of the total isolates exhibited resistance to Cefotaxime. All oftheLegionellapneumophila,comprising 4.4%of the isolated species, wereresistant to Cefotaxime, Azithromycin, and Clindamycin.In contrast, 50% were resistant to Cefotaxime, Azithromycin, and Ceftriaxone. Of the Escherichia coli(4.4%, n=45) isolated,50% exhibited resistance to Cefotaxime, Clindamycin, Ceftriaxone, Amoxycillinand Sulfamethoxazole.The only isolate of Klebsiella sp. was demonstrated to be an ESBL producer. The isolation of multidrug resistant bacteria from cancer patients is of particular concern in Bangladesh where cancer and drug resistance are both common phenomena but treatment facilities are poor. To our knowledge this is the first report of the isolation of drug resistant bacteria from cancer patients from Dhaka city. Bangladesh J Microbiol, Volume 35 Number 1 June 2018, pp 61-66

scholarly journals Species Diversity of Environmental GIM-1-Producing Bacteria Collected during a Long-Term Outbreak

2016 ◽  
Vol 82 (12) ◽  
pp. 3605-3610 ◽  
Author(s):  
Andreas F. Wendel ◽  
Sofija Ressina ◽  
Susanne Kolbe-Busch ◽  
Klaus Pfeffer ◽  
Colin R. MacKenzie
Keyword(s):  
Resistance Genes ◽  
Multidrug Resistant ◽  
Hospital Environment ◽  
Resistant Bacteria ◽  
Environmental Sampling ◽  
Gram Negative Bacteria ◽  
Multidrug Resistant Bacteria ◽  
Gram Negative ◽  
Content Type

ABSTRACTReports of outbreaks concerning carbapenemase-producing Gram-negative bacteria in which the main source of transmission is the hospital environment are increasing. This study describes the results of environmental sampling in a protracted polyspecies metallo-beta-lactamase GIM-1 outbreak driven by plasmids and bacterial clones ofEnterobacter cloacaeandPseudomonas aeruginosain a tertiary care center. Environmental sampling targeting wet locations (especially sinks) was carried out on a surgical intensive care unit and on a medical ward on several occasions in 2012 and 2013. We were able to demonstrate 43blaGIM-1-carrying bacteria (mainly nonfermenters but alsoEnterobacteriaceae) that were either related or unrelated to clinical strains in 30 sinks and one hair washbasin. GIM-1 was found in 12 different species, some of which are described here as carriers of GIM-1. Forty out of 43 bacteria displayed resistance to carbapenems and, in addition, to various non-beta-lactam antibiotics. Colistin resistance was observed in twoE. cloacaeisolates with MICs above 256 mg/liter. TheblaGIM-1gene was harbored in 12 different class 1 integrons, some without the typical 3′ end. TheblaGIM-1gene was localized on plasmids in five isolates.In vitroplasmid transfer by conjugation was successful in one isolate. The environment, with putatively multispecies biofilms, seems to be an important biological niche for multidrug-resistant bacteria and resistance genes. Biofilms may serve as a “melting pot” for horizontal gene transfer, for dissemination into new species, and as a reservoir to propagate future hospital outbreaks.IMPORTANCEIn Gram-negative bacteria, resistance to the clinically relevant broad-spectrum carbapenem antibiotics is a major public health concern. Major reservoirs for these resistant organisms are not only the gastrointestinal tracts of animals and humans but also the (hospital) environment. Due to the difficulty in eradicating biofilm formation in the latter, a sustained dissemination of multidrug-resistant bacteria from the environment can occur. In addition, horizontal transfer of resistance genes on mobile genetic elements within biofilms adds to the total “resistance gene pool” in the environment. To gain insight into the transmission pathways of a rare and locally restricted carbapenemases resistance gene (blaGIM-1), we analyzed the genetic background of theblaGIM-1gene in environmental bacteria during a long-term polyspecies outbreak in a German hospital.

scholarly journals Antibiotic Resistant Bacterial Isolates from Captive Green Turtles andIn VitroSensitivity to Bacteriophages

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
Alessandro Delli Paoli Carini ◽  
Ellen Ariel ◽  
Jacqueline Picard ◽  
Lisa Elliott
Keyword(s):  
Rapid Evolution ◽  
Chelonia Mydas ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Green Turtles ◽  
Resistant Genes ◽  
Resistance Rates

This study aimed to test multidrug resistant isolates from hospitalised green turtles(Chelonia mydas)and their environment in North Queensland, Australia, forin vitrosusceptibility to bacteriophages. Seventy-one Gram-negative bacteria were isolated from green turtle eye swabs and water samples. Broth microdilution tests were used to determine antibiotic susceptibility. All isolates were resistant to at least two antibiotics, with 24% being resistant to seven of the eight antibiotics. Highest resistance rates were detected to enrofloxacin (77%) and ampicillin (69.2%). More than 50% resistance was also found to amoxicillin/clavulanic acid (62.5%), ceftiofur (53.8%), and erythromycin (53.3%). All the enriched phage filtrate mixtures resulted in the lysis of one or more of the multidrug resistant bacteria, includingVibrio harveyiandV. parahaemolyticus. These results indicate that antibiotic resistance is common in Gram-negative bacteria isolated from hospitalised sea turtles and their marine environment in North Queensland, supporting global concern over the rapid evolution of multidrug resistant genes in the environment. Using virulent bacteriophages as antibiotic alternatives would not only be beneficial to turtle health but also prevent further addition of multidrug resistant genes to coastal waters.

scholarly journals Emergence of multidrug-resistant bacteria isolated from surgical site infection in dogs and cats

2020 ◽  
Vol 72 (4) ◽  
pp. 1213-1220
Author(s):  
C.M.M. Corsini ◽  
V.O. Silva ◽  
O.V. Carvalho ◽  
R.V. Sepúlveda ◽  
F.L. Valente ◽  
...  
Keyword(s):  
Antimicrobial Prophylaxis ◽  
Surgical Site Infections ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Gram Negative Bacteria ◽  
Multidrug Resistant Bacteria ◽  
Methicillin Resistant ◽  
Amoxicillin Clavulanic Acid ◽  
Veterinary Hospital ◽  
Surgical Clinic

ABSTRACT Surgical site infections (SSIs) and antimicrobial resistance among pathogens causing SSI are a growing concern in veterinary hospitals. One major reason, the widespread use of antimicrobials, has led to increased incidence of SSIs. This study identified bacteria and resistance profiles to antimicrobials in the SSI cases diagnosed at the Surgical Clinic of Small Animals in the Veterinary Hospital, Federal University of Viçosa, Brazil. The main genus identified was Staphylococcus, followed by Escherichia, Enterococcus, Bacillus, Shigella, Citrobacter, Proteus, Morganella, Serratia, Enterobacter, Pseudomonas and Klebsiella were also found, but in small number. The results indicated the predominance of Gram-negative bacteria among the collected samples. Most of isolates identified were resistant to more than one of the following antimicrobials: ampicillin, tetracycline, enrofloxacin, amoxicillin/clavulanic acid and cephalotin. Of the 17 Staphylococcus sp. isolates, two (11.8%) were methicillin-resistant Staphylococcus aureus (MRSA) and 11 (64.7%) of them were methicillin-resistant Staphylococcus pseudintermedius (MRSP). There were bacterial genera identified with resistance to all tested antimicrobials in different proportions. This should alert veterinary hospitals to the emergence of multidrug-resistant bacteria and to the requirement for the revision of surgical protocols with regard to antimicrobial prophylaxis and therapy.

scholarly journals Trends of Bloodstream Infections in a University Greek Hospital during a Three-Year Period: Incidence of Multidrug-Resistant Bacteria and Seasonality in Gram-negative Predominance

2017 ◽  
Vol 66 (2) ◽  
pp. 171-180 ◽  
Author(s):  
Fevronia Kolonitsiou ◽  
Matthaios Papadimitriou-Olivgeris ◽  
Anastasia Spiliopoulou ◽  
Vasiliki Stamouli ◽  
Vasileios Papakostas ◽  
...  
Keyword(s):  
Bloodstream Infections ◽  
Multidrug Resistant ◽  
Blood Cultures ◽  
Diffusion Method ◽  
Resistant Bacteria ◽  
Gram Negative Bacteria ◽  
Multidrug Resistant Bacteria ◽  
Gram Positive ◽  
Gram Negative ◽  
Carbapenem Resistant

The aim of the study was to assess the epidemiology, the incidence of multidrug-resistant bacteria and bloodstream infections’ (BSIs) seasonality in a university hospital. This retrospective study was carried out in the University General Hospital of Patras, Greece, during 2011–13 y. Blood cultures from patients with clinical presentation suggestive of bloodstream infection were performed by the BacT/ALERT System. Isolates were identified by Vitek 2 Advanced Expert System. Antibiotic susceptibility testing was performed by the disk diffusion method and E-test. Resistance genes (mecA in staphylococci; vanA/vanB/vanC in enterococci; blaKPC/blaVIM/blaNDM in Klebsiella spp.) were detected by PCR. In total, 4607 (9.7%) blood cultures were positive from 47451 sets sent to Department of Microbiology, representing 1732 BSIs. Gram-negative bacteria (52.3%) were the most commonly isolated, followed by Gram-positive (39.5%), fungi (6.6%) and anaerobes bacteria (1.8%). The highest contamination rate was observed among Gram-positive bacteria (42.3%). Among 330 CNS and 150 Staphylococcus aureus, 281 (85.2%) and 60 (40.0%) were mecA-positive, respectively. From 113 enterococci, eight were vanA, two vanB and two vanC-positives. Of the total 207 carbapenem-resistant Klebsiella pneumoniae (73.4%), 202 carried blaKPC, four blaKPC and blaVIM and one blaVIM. A significant increase in monthly BSIs’ incidence was shown (R2: 0.449), which may be attributed to a rise of Gram-positive BSIs (R2: 0.337). Gram-positive BSIs were less frequent in spring (P < 0.001), summer (P < 0.001), and autumn (P < 0.001), as compared to winter months, while Gram-negative bacteria (P < 0.001) and fungi (P < 0.001) were more frequent in summer months. BSIs due to methicillin resistant S. aureus and carbapenem-resistant Gram-negative bacteria increased during the study period. The increasing incidence of BSIs can be attributed to an increase of Gram-positive BSI incidence, even though Gram-negative bacteria remained the predominant ones. Seasonality may play a role in the predominance of Gram-negative’s BSI.

scholarly journals Antimicrobial Resistance in Hospitalized Surgical Patients: a Silently Emerging Public Health Concern in Benin.

2020 ◽  
Author(s):  
Carine Laurence YEHOUENOU ◽  
Arsène A. KPANGON ◽  
Dissou AFFOLABI ◽  
Hector RODRIGUEZ-VILLALOBOS ◽  
Françoise Van Bambeke ◽  
...  
Keyword(s):  
Gastrointestinal Surgery ◽  
Surgical Site Infections ◽  
Multidrug Resistant ◽  
Public Hospitals ◽  
Health Concern ◽  
Diffusion Method ◽  
Resistant Bacteria ◽  
Gram Negative Bacteria ◽  
Strict Adherence ◽  
Gram Negative

Abstract Background: Surgical site infections are related to high morbidity, mortality and healthcare costs. As the emergence of multidrug-resistant bacterial pathogens in hospitals is becoming a worldwide challenge for surgeons who treat healthcare-associated infections, we wished to identify the causative agents involved in surgical site infections and their susceptibility pattern in six public hospitals in Benin. Methods: Using standard microbiological procedures, we processed pus specimens collected from obstetrics and gastrointestinal surgery wards. Mass spectrometry (MALDI-TOF) was used for confirmation. The antibiotic susceptibility test firstly used the Kirby-Bauer disc diffusion method. The secondary test by microdilution used the Beckton Dickinson Phoenix automated system (Becton Dickinson Diagnostic, USA). Results: We included 304 patients (mean age 32 ± 11 years), whose median length of stay was 9 days. A total of 259 wound swabs (85.2%) had positive aerobic bacterial growth. In obstetrics S. aureus (28.5%, n=42) was the most common isolate. In contrast, Gram-negative bacteria (GNB) were predominant in gastrointestinal surgery. The most dominant being E.coli (38.4%, n=31). Overall, 90.8% (n=208) of aerobic bacteria were multidrug resistant. Two-third of S. aureus (65.3%, n= 32) were methicillin-resistant Staphylococcus aureus (MRSA), three of which carried both MRSA and induced clindamycin resistance (ICR). GNB showed high resistance to ceftazidime, ceftriaxone and cefepime. Extended-spectrum beta-lactamases were presented by 69.4% of E.coli (n=43/62) and 83.3% of K. pneumoniae (n=25/30). Overall, twelve Gram negative bacteria (5.24%) isolates showed resistance to at least one carbapenem. No isolates showed a wild-type susceptible phenotype.Conclusion: This study shows the alarming prevalence of multidrug resistant organisms from surgical site infections in Benin hospitals. To reduce the spread of these multidrug-resistant bacteria, periodic surveillance of surgical site infections and strict adherence to good hand-hygiene practice are essential.

scholarly journals Detection of Multidrug Resistant Gram Negative Bacteria in Healthy Cattle from Maiduguri Metropolitan, Nigeria

2020 ◽  
pp. 68-76
Author(s):  
Adam Mustapha ◽  
Mustafa Alhaji Isa ◽  
Ibrahim Yusuf Ngoshe ◽  
Hashidu Bala
Keyword(s):  
Antibiotic Resistance ◽  
Clinical Laboratory ◽  
Resistance Index ◽  
Multidrug Resistant ◽  
Diffusion Method ◽  
Resistant Bacteria ◽  
Gram Negative Bacteria ◽  
Salmonella Spp ◽  
Gram Negative ◽  
Healthy Cattle

Aim: Prevalence of multidrug resistant bacteria on apparently health animals has turned antibiotic resistance to multifaceted process and threatens global food security and public health. The aim of the present study was to investigate the resistance profile of isolates from apparently healthy cattle in Maiduguri, Nigeria. Methodology: A total of 120 nasal swab samples were collected from cattle. Colony identification was according to the guidelines of Bergey’s Manual of Determinative Bacteriology. The susceptibility pattern of the isolates was conducted on the identified isolates according to the Modified Kirby-Baur disc diffusion method on Muller-Hilton agar and interpreted according to the procedures of Clinical Laboratory Standards Institute (CLSI, 2018) guidelines. Multiple Antibiotic Resistance Index (MARI) was calculated using the formula, MARI=a/b where “a” is the number of antibiotic resisted and “b” is the total number of antibiotic used in the study. Results: Of the total samples (120) from cattle 96 (80%) detected the following isolates; E. coli was the most commonly recovered isolates (33, 34.4%), followed by Klebsiella spp (28, 29.2%), Salmonella spp (21, 21.9%) and Pseudomonas aeruginosa (14, 14.5%). In this study, all the recovered isolates were found to be multidrug resistant gram negative bacteria, with highest resistance was shown by Salmonella spp. The high MARI observed in all the isolates in this study ranging from 0.7 to 0.9. MARI value of 0.2 > is suggests multiple antibiotic resistant bacteria and indicate presence of highly resistant bacteria. Conclusion: The study indicates highly resistant bacteria are carried by healthy food animals. Thus, there is need for continued monitoring of antibiotics use in animal husbandry to prevent further spread of resistance in Maiduguri, Nigeria.

Oral, nasopharyngeal, and gut decontamination in the ICU

2016 ◽  
Author(s):  
Evelien Oostdijk ◽  
Marc Bonten
Keyword(s):  
Digestive Tract ◽  
Antibiotic Use ◽  
Multidrug Resistant ◽  
Selective Decontamination ◽  
Resistant Bacteria ◽  
Gram Negative Bacteria ◽  
Detailed Data ◽  
Multidrug Resistant Bacteria ◽  
Gram Negative ◽  
Selective Oropharyngeal Decontamination

Many infections are caused by enteric bacilli, presumably from endogenous origin. Selective decontamination of the digestive tract (SDD) was developed to selectively eliminate the aerobic Gram-negative bacilli from the digestive tract, leaving the anaerobic flora unaffected. As an alternative to SDD, investigators have evaluated the effects of selective oropharyngeal decontamination (SOpD) alone. Most detailed data on the effects of SDD and SOpD in ICU-patients come from two studies performed in Dutch ICUs. The Dutch studies provide strong evidence that SDD and SOpD reduce ICUmortality, ICU-acquired bacteraemia with Gram-negative bacteria, and systemic antibiotic use. Although successful application has been reported from several solitary ICUs across Europe, it is currently unknown to what extent these effects can be achieved in settings with different bacterial ecology. More studies are needed on the use of SDD or SOpD as a measure to control outbreaks with multidrug resistant bacteria.

scholarly journals Screening Repurposing Libraries for Identification of Drugs with Novel Antifungal Activity

2020 ◽  
Vol 64 (9) ◽  
Author(s):  
Gina Wall ◽  
Jose L. Lopez-Ribot
Keyword(s):  
Antifungal Activity ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Alternative Pathway ◽  
Drug Repurposing ◽  
Pathogenic Fungi ◽  
Multidrug Resistant ◽  
Modern Medicine ◽  
Antifungal Drugs ◽  
Promising Alternative

ABSTRACT Fungal organisms are ubiquitous in nature, and progress of modern medicine is creating an expanding number of severely compromised patients susceptible to a variety of opportunistic fungal infections. These infections are difficult to diagnose and treat, leading to high mortality rates. The limited antifungal arsenal, the toxicity of current antifungal drugs, the development of resistance, and the emergence of new multidrug-resistant fungi, all highlight the urgent need for new antifungal agents. Unfortunately, the development of a novel antifungal is a rather long and expensive proposition, and no new classes of antifungal agents have reached the market in the last 2 decades. Drug repurposing, or finding new indications for old drugs, represents a promising alternative pathway to drug development that is particularly appealing within the academic environment. In the last few years, there has been a growing interest in repurposing approaches in the antifungal arena, with multiple groups of investigators having performed screenings of different repurposing libraries against different pathogenic fungi in search for drugs with previously unrecognized antifungal effects. Overall, these repurposing efforts may lead to the fast deployment of drugs with novel antifungal activity, which can rapidly bring benefits to patients, while at the same time reducing health care costs.

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