Antimicrobial Peptides from Rat-Tailed Maggots of the Drone Fly Eristalis tenax Show Potent Activity against Multidrug-Resistant Gram-Negative Bacteria

The spread of multidrug-resistant Gram-negative bacteria is an increasing threat to human health, because novel compound classes for the development of antibiotics have not been discovered for decades. Antimicrobial peptides (AMPs) may provide a much-needed breakthrough because these immunity-related defense molecules protect many eukaryotes against Gram-negative pathogens. Recent concepts in evolutionary immunology predict the presence of potent AMPs in insects that have adapted to survive in habitats with extreme microbial contamination. For example, the saprophagous and coprophagous maggots of the drone fly Eristalis tenax (Diptera) can flourish in polluted aquatic habitats, such as sewage tanks and farmyard liquid manure storage pits. We used next-generation sequencing to screen the E. tenax immunity-related transcriptome for AMPs that are synthesized in response to the injection of bacterial lipopolysaccharide. We identified 22 AMPs and selected nine for larger-scale synthesis to test their activity against a broad spectrum of pathogens, including multidrug-resistant Gram-negative bacteria. Two cecropin-like peptides (EtCec1-a and EtCec2-a) and a diptericin-like peptide (EtDip) displayed strong activity against the pathogens, even under simulated physiological conditions, and also achieved a good therapeutic window. Therefore, these AMPs could be used as leads for the development of novel antibiotics.

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Circumventing colistin resistance by combining colistin and antimicrobial peptides to kill colistin-resistant and multidrug-resistant Gram-negative bacteria

Journal of Global Antimicrobial Resistance ◽

10.1016/j.jgar.2020.05.013 ◽

2020 ◽

Vol 22 ◽

pp. 706-712

Author(s):

Kaitlin S. Witherell ◽

Jason Price ◽

Ashok D. Bandaranayake ◽

James Olson ◽

Douglas R. Call

Keyword(s):

Antimicrobial Peptides ◽

Multidrug Resistant ◽

Gram Negative Bacteria ◽

Colistin Resistance ◽

Gram Negative

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Identification of Ly2 members as antimicrobial peptides from zebrafish Danio rerio

Bioscience Reports ◽

10.1042/bsr20160265 ◽

2017 ◽

Vol 37 (1) ◽

Cited By ~ 6

Author(s):

Xuemin Liu ◽

Xuwen Cao ◽

Su Wang ◽

Guangdong Ji ◽

Shicui Zhang ◽

...

Keyword(s):

Antimicrobial Peptides ◽

Recombinant Proteins ◽

Mammalian Cells ◽

Multidrug Resistant ◽

Scatchard Analysis ◽

Gram Negative Bacteria ◽

Gram Positive ◽

Gram Negative ◽

E Coli ◽

Gram Positive Bacteria

The emergence of multidrug-resistant (MDR) microbes caused by overuse of antibiotics leads to urgent demands for novel antibiotics exploration. Our recent data showed that Ly2.1–3 (a novel lymphocyte antigen 6 (Ly6) gene cluster) were proteins with cationic nature and rich in cysteine content, that are characteristic of antimicrobial peptides (AMPs) and their expression were all significantly up-regulated after challenge with lipopolysaccharide (LPS). These strongly suggested that Ly2.1–3 are potential AMPs, but firm evidence are lacking. Here, we clearly showed that the recombinant proteins of Ly2.1–3 were capable of killing Gram-negative bacteria Aeromonas hydrophila and Escherichia coli, while they had little bactericidal activity against the Gram-positive bacteria Staphylococcus aureus and Bacillus subtilis. We also showed that recombinant proteins Ly2.1–3 (rLy2.1–3) were able to bind to the Gram-negative bacteria A. hydrophila, E. coli and the microbial signature molecule LPS, but not to the Gram-positive bacteria S. aureus and B. subtilis as well as the microbial signature molecule LTA. Moreover, the Scatchard analysis revealed that rLy2.1–3 could specifically bind to LPS. Finally, we found that Ly2.1–3 were not cytotoxic to mammalian cells. All these together indicate that Ly2.1–3 can function as AMPs.

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Tridecaptin-inspired antimicrobial peptides with activity against multidrug-resistant Gram-negative bacteria

MedChemComm ◽

10.1039/c9md00031c ◽

2019 ◽

Vol 10 (3) ◽

pp. 484-487 ◽

Cited By ~ 5

Author(s):

Ross D. Ballantine ◽

Conor E. McCallion ◽

Elie Nassour ◽

Sima Tokajian ◽

Stephen A. Cochrane

Keyword(s):

Antimicrobial Peptides ◽

Multidrug Resistant ◽

Gram Negative Bacteria ◽

Gram Negative

New tridecaptin analogues are cheaper to make and retain strong Gram-negative activity.

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A novel chemical biology and computational approach to expedite the discovery of new-generation polymyxins against life-threatening Acinetobacter baumannii

Chemical Science ◽

10.1039/d1sc03460j ◽

2021 ◽

Author(s):

Xukai Jiang ◽

Nitin A. Patil ◽

Mohammad A. K. Azad ◽

Hasini Wickremasinghe ◽

Heidi Yu ◽

...

Keyword(s):

Public Health ◽

Chemical Biology ◽

Multidrug Resistant ◽

Computational Approach ◽

Gram Negative Bacteria ◽

Global Public Health ◽

Gram Negative ◽

Life Threatening ◽

New Generation ◽

Novel Antibiotics

Multidrug-resistant Gram-negative bacteria have been an urgent threat to global public health. Novel antibiotics are desperately needed to combat these 'superbugs'.

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Proteomic response of Escherichia coli to a membrane lytic and iron chelating truncated Amaranthus tricolor defensin

BMC Microbiology ◽

10.1186/s12866-021-02176-4 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Tessa B. Moyer ◽

Ashleigh L. Purvis ◽

Andrew J. Wommack ◽

Leslie M. Hicks

Keyword(s):

Escherichia Coli ◽

Antibacterial Activity ◽

Antimicrobial Peptides ◽

Mechanism Of Action ◽

Gram Negative Bacteria ◽

Amaranthus Tricolor ◽

Core Motif ◽

Gram Negative ◽

E Coli ◽

Membrane Lysis

Abstract Background Plant defensins are a broadly distributed family of antimicrobial peptides which have been primarily studied for agriculturally relevant antifungal activity. Recent studies have probed defensins against Gram-negative bacteria revealing evidence for multiple mechanisms of action including membrane lysis and ribosomal inhibition. Herein, a truncated synthetic analog containing the γ-core motif of Amaranthus tricolor DEF2 (Atr-DEF2) reveals Gram-negative antibacterial activity and its mechanism of action is probed via proteomics, outer membrane permeability studies, and iron reduction/chelation assays. Results Atr-DEF2(G39-C54) demonstrated activity against two Gram-negative human bacterial pathogens, Escherichia coli and Klebsiella pneumoniae. Quantitative proteomics revealed changes in the E. coli proteome in response to treatment of sub-lethal concentrations of the truncated defensin, including bacterial outer membrane (OM) and iron acquisition/processing related proteins. Modification of OM charge is a common response of Gram-negative bacteria to membrane lytic antimicrobial peptides (AMPs) to reduce electrostatic interactions, and this mechanism of action was confirmed for Atr-DEF2(G39-C54) via an N-phenylnaphthalen-1-amine uptake assay. Additionally, in vitro assays confirmed the capacity of Atr-DEF2(G39-C54) to reduce Fe3+ and chelate Fe2+ at cell culture relevant concentrations, thus limiting the availability of essential enzymatic cofactors. Conclusions This study highlights the utility of plant defensin γ-core motif synthetic analogs for characterization of novel defensin activity. Proteomic changes in E. coli after treatment with Atr-DEF2(G39-C54) supported the hypothesis that membrane lysis is an important component of γ-core motif mediated antibacterial activity but also emphasized that other properties, such as metal sequestration, may contribute to a multifaceted mechanism of action.

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Outcomes and Risk Factors in Prosthetic Joint Infections by multidrug-resistant Gram-negative Bacteria: A Retrospective Cohort Study

Antibiotics ◽

10.3390/antibiotics10030340 ◽

2021 ◽

Vol 10 (3) ◽

pp. 340

Author(s):

Raquel Bandeira da Silva ◽

Mauro José Salles

Keyword(s):

Risk Factors ◽

Treatment Failure ◽

Treatment Outcomes ◽

Revision Arthroplasty ◽

Multidrug Resistant ◽

Gram Negative Bacteria ◽

Gram Negative ◽

Postoperative Hematoma ◽

Prosthetic Joint ◽

Prosthetic Joint Infections

Gram-negative bacteria (GNB), including multidrug-resistant (MDR) pathogens, are gaining importance in the aetiology of prosthetic joint infection (PJI). This retrospective observational study identified independent risk factors (RFs) associated with MDR-GNB PJI and their influence on treatment outcomes. We assessed MDR bacteria causing hip and knee PJIs diagnosed at a Brazilian tertiary hospital from January 2014 to July 2018. RFs associated with MDR-GNB PJI were estimated by bivariate and multivariate analyses using prevalence ratios (PRs) with significance at p < 0.05. Kaplan–Meier analysis was performed to evaluate treatment outcomes. Overall, 98 PJI patients were analysed, including 56 with MDR-GNB and 42 with other bacteria. Independent RFs associated with MDR-GNB PJI were revision arthroplasty (p = 0.002), postoperative hematoma (p < 0.001), previous orthopaedic infection (p = 0.002) and early infection (p = 0.001). Extensively drug-resistant GNB (p = 0.044) and comorbidities (p = 0.044) were independently associated with MDR-GNB PJI treatment failure. In sum, MDR-GNB PJI was independently associated with previous orthopaedic surgery, postoperative local complications and pre-existing infections and was possibly related to selective pressure on bacterial skin colonisation by antibiotics prescribed for early PJI. Infections due to MDR-GNB and comorbidities were associated with higher treatment failure rates.

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OMN6 a novel bioengineered peptide for the treatment of multidrug resistant Gram negative bacteria

Scientific Reports ◽

10.1038/s41598-021-86155-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Shira Mandel ◽

Janna Michaeli ◽

Noa Nur ◽

Isabelle Erbetti ◽

Jonathan Zazoun ◽

...

Keyword(s):

Mechanism Of Action ◽

Antimicrobial Agents ◽

Cyclic Peptide ◽

Safety Margin ◽

Multidrug Resistant ◽

Gram Negative Bacteria ◽

Antibiotic Resistant ◽

Gram Negative ◽

Development Of Resistance ◽

Cecropin A

AbstractNew antimicrobial agents are urgently needed, especially to eliminate multidrug resistant Gram-negative bacteria that stand for most antibiotic-resistant threats. In the following study, we present superior properties of an engineered antimicrobial peptide, OMN6, a 40-amino acid cyclic peptide based on Cecropin A, that presents high efficacy against Gram-negative bacteria with a bactericidal mechanism of action. The target of OMN6 is assumed to be the bacterial membrane in contrast to small molecule-based agents which bind to a specific enzyme or bacterial site. Moreover, OMN6 mechanism of action is effective on Acinetobacter baumannii laboratory strains and clinical isolates, regardless of the bacteria genotype or resistance-phenotype, thus, is by orders-of-magnitude, less likely for mutation-driven development of resistance, recrudescence, or tolerance. OMN6 displays an increase in stability and a significant decrease in proteolytic degradation with full safety margin on erythrocytes and HEK293T cells. Taken together, these results strongly suggest that OMN6 is an efficient, stable, and non-toxic novel antimicrobial agent with the potential to become a therapy for humans.

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832. Assessment of Risk Factors Associated with Wide-resistance Gram-negative Bacteria Infections

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.1021 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S457-S457

Author(s):

Henry Pablo Lopes Campos e Reis ◽

Ana Beatriz Ferreira Rodrigues ◽

Julio César Castro Silva ◽

Lia Pinheiro de Lima ◽

Talita Lima Quinaher ◽

...

Keyword(s):

Risk Factors ◽

Mechanical Ventilation ◽

Univariate Analysis ◽

Multidrug Resistant ◽

University Hospital ◽

Gram Negative Bacteria ◽

Multiresistant Pathogens ◽

Gram Negative ◽

Contact Isolation ◽

Bladder Catheter

Abstract Background Enterobacteria and multidrug-resistant non-fermenting Gram-negative bacilli present a challenge in the management of invasive infections, leading to mortality rates due to their limited therapeutic arsenal. The objective of this work was to analyze risk factors that may be associated with these infections, for a better situational mapping and assertive decision-making in a university hospital in Brazil. Methods The study was conducted between January and September 2019, with 167 patients in contact isolation at a university hospital in Brazil. Potential outcome-related variables for wide-resistance Gram-negative bacteria (BGN) infections were evaluated. Risk factors were identified from univariate statistical analysis using Fisher’s test. Results 51 (30.5%) out of 167 patients in contact isolation evolved with wide-resistance BGN infection. Risk factors in univariate analysis were age, hospital unit and previous use of invasive devices. Patients aged up to 59 years were more likely to progress to infection than those aged over 60 years (p 0.0274, OR 2.2, 95% CI 1.1-4.5). Those admitted to the oncohematology (p < 0.001, OR 32.5, Cl 9.1-116.3) and intensive care unit (p < 0.001, OR 28.0, Cl 3.5-225.9) units were more likely to develop this type of infection. The least likely were those admitted to a kidney transplant unit (p 0.0034, OR 15.33, Cl 1.8-131.0). Prior use of mechanical ventilation (p 0.0058, OR 12.2, Cl 2.0-76.1) and delayed bladder catheter (p 0.0266, OR 5.0, Cl 1.2-20.1) in patients with respiratory and urinary tract infection, respectively, were also reported as risk factors related to these infections. The gender of the patients was not significant for the study. Conclusion This study determined that variables such as age, hospitalization unit, use of mechanical ventilation and delayed bladder catheter could be considered important risk factors in triggering the infectious process by wide-resistant gram-negative bacteria. Thus, the analysis of these factors becomes a great foundation to prevent the development of multiresistant pathogens through prevention strategies, prophylaxis management and more targeted empirical therapies. Disclosures All Authors: No reported disclosures

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