A New Surface Charge Neutralizing Nano-Adjuvant to Potentiate Polymyxins in Killing Mcr-1 Mediated Drug-Resistant Escherichia coli

Resistance to polymyxins when treating multidrug-resistant (MDR) Gram-negative bacterial infections limit therapeutic options. Here, we report the synthesis of a nickel (Ni) doped Zinc oxide (NZO) combined with black phosphorus (BP) (NZB) nanocomposite and its synergistic action with polymyxin B (PolB) against polymyxin-resistant Escherichia coli harboring mobilized colistin resistance (mcr-1) gene. NZB and PolB combination therapy expressed a specific and strong synergy against Mcr-1 expressing E. coli cells. The underlying mechanism of the synergy is the charge neutralization of the E. coli cell surface by NZB, resulting in a more feasible incorporation of PolB to E. coli. The synergistic concentration of NZB with PolB was proved biocompatible. Thus, the NZB is the first biocompatible nano-adjuvant to polymyxins against polymyxin-resistant E. coli cells, recognizing the physical status of bacteria instead of known adjuvants targeting cellular gene products. Therefore, NZB has the potential to revive polymyxins as leading last-resort antibiotics to combat polymyxin-resistant Gram-negative bacterial infections.

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Transcriptome changes and polymyxin resistance of acid-adapted Escherichia coli O157:H7 ATCC 43889

Gut Pathogens ◽

10.1186/s13099-020-00390-5 ◽

2020 ◽

Vol 12 (1) ◽

Author(s):

Daekeun Hwang ◽

Seung Min Kim ◽

Hyun Jung Kim

Keyword(s):

Escherichia Coli ◽

Acid Treatment ◽

Bacterial Infections ◽

Acid Tolerance ◽

Polymyxin B ◽

Multidrug Resistant ◽

Health Concern ◽

E Coli ◽

Tolerance Response ◽

Acid Tolerant

Abstract Background Acid treatment is commonly used for controlling or killing pathogenic microorganisms on medical devices and environments; however, inadequate acid treatment may cause acid tolerance response (ATR) and offer cross-protection against environmental stresses, including antimicrobials. This study aimed to characterise an Escherichia coli strain that can survive in the acidic gastrointestinal environment. Results We developed an acid-tolerant E. coli O157:H7 ATCC 43889 (ATCC 43889) strain that can survive at pH 2.75 via cell adaptation in low pH conditions. We also performed RNA sequencing and qRT-PCR to compare differentially expressed transcripts between acid-adapted and non-adapted cells. Genes related to stress resistance, including kdpA and bshA were upregulated in the acid-adapted ATCC 43889 strain. Furthermore, the polymyxin resistance gene arnA was upregulated in the acid-adapted cells, and resistance against polymyxin B and colistin (polymyxin E) was observed. As polymyxins are important antibiotics, effective against multidrug-resistant gram-negative bacterial infections, the emergence of polymyxin resistance in acid-adapted E. coli is a serious public health concern. Conclusion The transcriptomic and phenotypic changes analysed in this study during the adaptation of E. coli to acid environments can provide useful information for developing intervention technologies and mitigating the risk associated with the emergence and spread of antimicrobial resistance.

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Resveratrol enhances the antimicrobial effect of polymyxin B on Klebsiella pneumoniae and Escherichia coli isolates with polymyxin B resistance

BMC Microbiology ◽

10.1186/s12866-020-01995-1 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Li Liu ◽

Jingyi Yu ◽

Xiaofei Shen ◽

Xingwei Cao ◽

Qing Zhan ◽

...

Keyword(s):

Escherichia Coli ◽

Klebsiella Pneumoniae ◽

Bacterial Infections ◽

Antimicrobial Effect ◽

Polymyxin B ◽

Multidrug Resistant ◽

Bacterial Strains ◽

Gram Negative ◽

Optimal Drug

Abstract Background Multidrug resistant (MDR) Gram-negative bacterial infections are a serious threat to human health due to the lack of effective treatments. In this study, we selected 50 Gram-negative bacterial strains, including 26 strains of Klebsiella pneumoniae and 24 strains of Escherichia coli, to explore whether resveratrol and polymyxin B have a synergistic killing effect. Results MIC values against polymyxin B were ≥ 4 μg/mL for 44 of the strains and were 2 μg/mL for the other 6 strains. MICs against polymyxin B in the isolates tested were significantly reduced by the addition of resveratrol. The degree of decline depended on the bacteria, ranging from 1/2 MIC to 1/512 MIC, and the higher the concentration of resveratrol, the greater the decrease. Checkerboard analysis indicated a synergistic effect between resveratrol and polymyxin B; the optimal drug concentration for different bacteria was different, that of resveratrol ranging from 32 μg/mL to 128 μg/mL. Subsequent time-kill experiments showed that a combination of polymyxin B and resveratrol was more effective in killing bacteria. Conclusions Our in vitro studies have shown that resveratrol can increase the sensitivity of MDR bacterial strains to polymyxin B, suggesting a potential new approach to the treatment of MDR infections.

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Three-Year Trend in Escherichia coli Antimicrobial Resistance among Children’s Urine Cultures in an Italian Metropolitan Area

Children ◽

10.3390/children8070597 ◽

2021 ◽

Vol 8 (7) ◽

pp. 597

Author(s):

Luca Pierantoni ◽

Laura Andreozzi ◽

Simone Ambretti ◽

Arianna Dondi ◽

Carlotta Biagi ◽

...

Keyword(s):

Escherichia Coli ◽

Metropolitan Area ◽

Bacterial Infections ◽

Asymptomatic Bacteriuria ◽

Multidrug Resistant ◽

Resistance Rate ◽

First Line ◽

E Coli ◽

First Line Therapy ◽

Tract Infections

Urinary tract infections (UTIs) are among the most common bacterial infections in children, and Escherichia coli is the main pathogen responsible. Several guidelines, including the recently updated Italian guidelines, recommend amoxicillin-clavulanic acid (AMC) as a first-line antibiotic therapy in children with febrile UTIs. Given the current increasing rates of antibiotic resistance worldwide, this study aimed to investigate the three-year trend in the resistance rate of E. coli isolated from pediatric urine cultures (UCs) in a metropolitan area of northern Italy. We conducted a retrospective review of E. coli-positive, non-repetitive UCs collected in children aged from 1 month to 14 years, regardless of a diagnosis of UTI, catheter colonization, urine contamination, or asymptomatic bacteriuria. During the study period, the rate of resistance to AMC significantly increased from 17.6% to 40.2% (p < 0.001). Ciprofloxacin doubled its resistance rate from 9.1% to 16.3% (p = 0.007). The prevalence of multidrug-resistant E. coli rose from 3.9% to 9.2% (p = 0.015). The rate of resistance to other considered antibiotics remained stable, as did the prevalence of extended spectrum beta-lactamases and extensively resistant E. coli among isolates. These findings call into question the use of AMC as a first-line therapy for pediatric UTIs in our population, despite the indications of recent Italian guidelines.

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Heterogeneous and Flexible Transmission ofmcr-1in Hospital-AssociatedEscherichia coli

mBio ◽

10.1128/mbio.00943-18 ◽

2018 ◽

Vol 9 (4) ◽

Cited By ~ 23

Author(s):

Yingbo Shen ◽

Zuowei Wu ◽

Yang Wang ◽

Rong Zhang ◽

Hong-Wei Zhou ◽

...

Keyword(s):

Escherichia Coli ◽

Genomic Analysis ◽

Multidrug Resistant ◽

Fluoroquinolone Resistance ◽

Gram Negative Bacteria ◽

Colistin Resistance ◽

Gram Negative ◽

Content Type ◽

E Coli ◽

Genes Encoding

ABSTRACTThe recent emergence of a transferable colistin resistance mechanism, MCR-1, has gained global attention because of its threat to clinical treatment of infections caused by multidrug-resistant Gram-negative bacteria. However, the possible transmission route ofmcr-1amongEnterobacteriaceaespecies in clinical settings is largely unknown. Here, we present a comprehensive genomic analysis ofEscherichia coliisolates collected in a hospital in Hangzhou, China. We found thatmcr-1-carrying isolates from clinical infections and feces of inpatients and healthy volunteers were genetically diverse and were not closely related phylogenetically, suggesting that clonal expansion is not involved in the spread ofmcr-1. Themcr-1gene was found on either chromosomes or plasmids, but in most of theE. coliisolates,mcr-1was carried on plasmids. The genetic context of the plasmids showed considerable diversity as evidenced by the different functional insertion sequence (IS) elements, toxin-antitoxin (TA) systems, heavy metal resistance determinants, and Rep proteins of broad-host-range plasmids. Additionally, the genomic analysis revealed nosocomial transmission ofmcr-1and the coexistence ofmcr-1with other genes encoding β-lactamases and fluoroquinolone resistance in theE. coliisolates. These findings indicate thatmcr-1is heterogeneously disseminated in both commensal and pathogenic strains ofE. coli, suggest the high flexibility of this gene in its association with diverse genetic backgrounds of the hosts, and provide new insights into the genome epidemiology ofmcr-1among hospital-associatedE. colistrains.IMPORTANCEColistin represents one of the very few available drugs for treating infections caused by extensively multidrug-resistant Gram-negative bacteria. The recently emergentmcr-1colistin resistance gene threatens the clinical utility of colistin and has gained global attention. Howmcr-1spreads in hospital settings remains unknown and was investigated by whole-genome sequencing ofmcr-1-carryingEscherichia coliin this study. The findings revealed extraordinary flexibility ofmcr-1in its spread among genetically diverseE. colihosts and plasmids, nosocomial transmission ofmcr-1-carryingE. coli, and the continuous emergence of novel Inc types of plasmids carryingmcr-1and newmcr-1variants. Additionally,mcr-1was found to be frequently associated with other genes encoding β-lactams and fluoroquinolone resistance. These findings provide important information on the transmission and epidemiology ofmcr-1and are of significant public health importance as the information is expected to facilitate the control of this significant antibiotic resistance threat.

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Prevalence of Colistin-Resistant, Carbapenem-Hydrolyzing Proteobacteria in Hospital Water Bodies and Out-Falls of West Bengal, India

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph17031007 ◽

2020 ◽

Vol 17 (3) ◽

pp. 1007

Author(s):

Taniya Bardhan ◽

Madhurima Chakraborty ◽

Bornali Bhattacharjee

Keyword(s):

Escherichia Coli ◽

Bacterial Infections ◽

West Bengal ◽

Environmental Water ◽

Multidrug Resistant ◽

P Value ◽

Hospital Wastewater ◽

E Coli ◽

Predominant Species ◽

Carbapenemase Gene

Indiscriminate use of antibiotics has resulted in a catastrophic increase in the levels of antibiotic resistance in India. Hospitals treat critical bacterial infections and thus can serve as reservoirs of multidrug resistant (MDR) bacteria. Hence, this study was conducted to gauge the prevalence patterns of MDR bacteria in hospital wastewater. Water samples collected from 11 hospitals and 4 environmental sources belonging to 5 most-densely populated districts of West Bengal, India were grown on MacConkey and Eosin Methylene Blue agar. A total of 84 (hospital-associated = 70, environmental water sources = 14) isolates were characterized. The predominant species found in water from hospital-associated areas (HAA) were Acinetobacter baumannii (22.9%), Escherichia coli (28.6 %), and Klebsiella pneumoniae (25.7%). Greater than 75% of the HAA isolates were found to be mcr-1 gene negative and colistinresistant. Meropenem non-susceptibility was also high among the HAA isolates at 58.6%, with the presence of the carbapenemase gene and blaNDM in 67.1% of the non-susceptible isolates. Among the three predominant species, significantly higher numbers of E. coli isolates were found to be non-susceptible to meropenem ((80%), p-value = 0.00432) and amikacin (AK (90%), p-value = 0.00037). This study provides evidence for the presence of high numbers of colistin-resistant and carbapenem-hydrolyzing Proteobacteriain hospital wastewater.

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Risk Factors and Prevalence of mcr-1-Positive Escherichia coli in Fecal Carriages Among Community Children in Southern Taiwan

Frontiers in Microbiology ◽

10.3389/fmicb.2021.748525 ◽

2021 ◽

Vol 12 ◽

Author(s):

Pin-Chieh Wu ◽

Ming-Fang Cheng ◽

Wan-Ling Chen ◽

Wan-Yu Hung ◽

Jiun-Ling Wang ◽

...

Keyword(s):

Risk Factors ◽

Escherichia Coli ◽

Bacterial Infections ◽

Medical Center ◽

Positive Association ◽

Multidrug Resistant ◽

E Coli ◽

Stool Samples ◽

Southern Taiwan ◽

Sequence Types

Colistin is the last resort antimicrobial for treating multidrug-resistant gram-negative bacterial infections. The plasmid-mediated colistin resistance gene, mcr-1, crucially influences colistin’s resistance transmission. Human fecal carriages of mcr-1-positive Escherichia coli (E. coli) were detected in many regions worldwide; however, only a few studies have focused on children. Therefore, we identified the prevalence and risk factors of mcr-1-positive E. coli in fecal carriages among community children in Southern Taiwan. In this study, 510 stool samples were collected from April 2016 to August 2019 from the pediatric department at a medical center in Southern Taiwan. These samples were collected within 3 days after admission and were all screened for the presence of the mcr-1 gene. Diet habits, travel history, pet contact, and medical history were also obtained from participants to analyze the risk factors of their fecal carriages to mcr-1-positive E. coli. Antimicrobial susceptibility testing was determined using the VITEK 2 system and the broth microdilution test. Twelve mcr-1-positive E. coli. were isolated from 2.4% of the fecal samples. Through multivariate analysis, frequent chicken consumption (at least 3 times per week) had a significantly positive association with the presence of mcr-1-positive E. coli in fecal carriages (adjust odds ratio 6.60, 95% confidence interval1.58– 27.62, p = 0.033). Additionally, multidrug resistance was more common in mcr-1-positive E. coli. (75.0% vs. 39.5%, p = 0.031) than in non-mcr-1-positive Escherichia coli. Furthermore, the percentage of extraintestinal pathogenic E. coli in mcr-1-positive isolates was 83.3%. Some multi-locus sequence types in our mcr-1-positive E. coli were also similar to those isolated from food animals in the literature. The prevalence of fecal carriages of mcr-1-positive E. coli was low among community children in Southern Taiwan. Our data shows that chicken consumption with a higher frequency increases the risk of mcr-1-positive E. coli. in fecal carriages.

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Antimicrobial Susceptibility Testing for Polymyxins: Challenges, Issues, and Recommendations

Journal of Clinical Microbiology ◽

10.1128/jcm.01390-18 ◽

2018 ◽

Vol 57 (4) ◽

Cited By ~ 12

Author(s):

Fereshteh Ezadi ◽

Abdollah Ardebili ◽

Reza Mirnejad

Keyword(s):

Bacterial Infections ◽

Susceptibility Testing ◽

Agar Medium ◽

Polymyxin B ◽

Multidrug Resistant ◽

Professional Organizations ◽

Gram Negative ◽

Microtiter Plates ◽

Critical Issues ◽

Polymyxin E

ABSTRACTPolymyxins, including polymyxin B and polymyxin E (colistin), are now increasingly being used worldwide to treat patients with multidrug-resistant (MDR) Gram-negative bacterial infections. This necessitates that laboratories employ an accurate and reliable method for the routine performance of polymyxin susceptibility testing. A number of reasons have accounted for the difficulties with susceptibility testing for the polymyxins, including their multicomponent composition, poor diffusion in the agar medium, adsorption to microtiter plates, the lack of a reliable susceptibility test, the lack of a specific breakpoint from professional organizations, the synergistic effect of polysorbate 80, and the development of heteroresistance. This minireview discusses such problems that impact the results of currently available susceptibility testing methods. We also provide emerging concepts on mechanisms of polymyxin resistance, including chromosomally and plasmid-mediatedmcr-related resistance. Broad-range investigations on such critical issues in relation to polymyxins can be beneficial for the implementation of effective treatment against MDR Gram-negative bacterial infections.

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Comparison of Polymyxin E and Polymyxin B as an Additive to Pulmonary Surfactant in Escherichia coli Pneumonia of Ventilated Neonatal Rabbits

Biomedicine Hub ◽

10.1159/000475877 ◽

2017 ◽

Vol 2 (2) ◽

pp. 1-9 ◽

Cited By ~ 4

Author(s):

Guido Stichtenoth ◽

Marie Haegerstrand-Björkman ◽

Gabi Walter ◽

Bim Linderholm ◽

Egbert Herting ◽

...

Keyword(s):

Escherichia Coli ◽

Bacterial Growth ◽

Pulmonary Surfactant ◽

Bacterial Infections ◽

Bacterial Load ◽

Polymyxin B ◽

Lung Compliance ◽

Antimicrobial Treatment ◽

E Coli ◽

Polymyxin E

Background: Ascending maternofetal bacterial infections often result in premature birth and neonatal respiratory distress. These neonates are treated with exogenous pulmonary surfactant (SF) and systemic antibiotics. Polymyxins are antimicrobiotic peptides that may bind to SF phospholipids. Objectives: Does topical administration of SF/polymyxin reduce bacterial growth in neonatal rabbit pneumonia and improve pulmonary function? Methods: Neonatal rabbits were tracheotomized and treated intratracheally with mixtures of porcine SF, SF/polymyxin E (PxE), or polymyxin B (PxB). Control animals received saline. Animals were then inoculated with Escherichia coli and ventilated for 4 h. During the experiment, peak insufflation pressures, dynamic lung compliance, and ECG were recorded. Pulmonary and renal bacterial load were determined. Lung histology was performed. Lung and kidney IL-8 were measured in subgroups. Results: Eighty-five animals were included in 2 experimental series, of which 78% survived 4 h of ventilation. E. coli inoculation caused severe neonatal pneumonia with median IL-8 levels of 2.2 ng/g in the lungs compared to a median of 0.2 ng/g in the lungs of the saline controls (p < 0.01). Lung compliance after 4 h was significantly increased at a mean of 0.48 ml/(kg·cm H2O) in the SF group and 0.43 in the SF + PxE group compared to 0.35 in the E. coli group (p < 0.01). In direct comparison, bacterial growth found in the E. coli group was reduced 20-fold in the SF + PxB group compared to 75-fold in the SF + PxE group. Conclusion: Addition of polymyxin to SF effectively promotes antimicrobial treatment and improves lung function in neonatal pneumonia of rabbits.

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Clinical use of intravenous polymyxin B for the treatment of patients with multidrug-resistant Gram-negative bacterial infections: An evaluation of the current evidence

Journal of Global Antimicrobial Resistance ◽

10.1016/j.jgar.2020.12.026 ◽

2021 ◽

Vol 24 ◽

pp. 342-359

Author(s):

Matthew E. Falagas ◽

Margarita Kyriakidou ◽

Georgios L. Voulgaris ◽

Filippos Vokos ◽

Sevasti Politi ◽

...

Keyword(s):

Bacterial Infections ◽

Polymyxin B ◽

Multidrug Resistant ◽

Current Evidence ◽

Clinical Use ◽

Gram Negative

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Correlated Transcriptional Responses Provide Insights into the Synergy Mechanisms of the Furazolidone, Vancomycin, and Sodium Deoxycholate Triple Combination in Escherichia coli

mSphere ◽

10.1128/msphere.00627-21 ◽

2021 ◽

Author(s):

Catrina Olivera ◽

Murray P. Cox ◽

Gareth J. Rowlands ◽

Jasna Rakonjac

Keyword(s):

Escherichia Coli ◽

Bacterial Infections ◽

Sodium Deoxycholate ◽

Multidrug Resistant ◽

Alternative Strategy ◽

Gram Negative Bacteria ◽

Triple Combination ◽

Transcriptional Responses ◽

Promising Alternative ◽

Gram Negative

Synergistic antibiotic combinations are a promising alternative strategy for developing effective therapies for multidrug-resistant bacterial infections. The synergistic combination of the existing antibiotics nitrofurans and vancomycin with sodium deoxycholate shows promise in inhibiting and killing multidrug-resistant Gram-negative bacteria.

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