Antimicrobial Peptides Derived From Insects Offer a Novel Therapeutic Option to Combat Biofilm: A Systematic Review

Biofilms form a complex layer with defined structures, that attach on biotic or abiotic surfaces, are tough to eradicate and tend to cause some resistance against most antibiotics. Several studies confirmed that biofilm-producing bacteria exhibit higher resistance compared to the planktonic form of the same species. Antibiotic resistance factors are well understood in planktonic bacteria which is not so in case of biofilm producing forms. This may be due to the lack of available drugs with known resistance mechanisms for biofilms. Existing antibiotics cannot eradicate most biofilms, especially of ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species). Insects produce complex and diverse set of chemicals for survival and defense. Antimicrobial peptides (AMPs), produced by most insects, generally have a broad spectrum of activity and the potential to bypass the resistance mechanisms of classical antibiotics. Besides, AMPs may well act synergistically with classical antibiotics for a double-pronged attack on infections. Thus, AMPs could be promising alternatives to overcome medically important biofilms, decrease the possibility of acquired resistance and treatment of multidrug-resistant pathogens including ESKAPE. The present review focuses on insect-derived AMPs with special reference to anti-biofilm-based strategies. It covers the AMP composition, pathways and mechanisms of action, the formation of biofilms, impact of biofilms on human diseases, current strategies as well as therapeutic options to combat biofilm with antimicrobial peptides from insects. In addition, the review also illustrates the importance of bioinformatics tools and molecular docking studies to boost the importance of select bioactive peptides those can be developed as drugs, as well as suggestions for further basic and clinical research.

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Mechanisms of Antimicrobial Resistance in ESKAPE Pathogens

BioMed Research International ◽

10.1155/2016/2475067 ◽

2016 ◽

Vol 2016 ◽

pp. 1-8 ◽

Cited By ~ 324

Author(s):

Sirijan Santajit ◽

Nitaya Indrawattana

Keyword(s):

Public Health ◽

Antimicrobial Resistance ◽

Antimicrobial Agents ◽

Multidrug Resistant ◽

Resistance Mechanisms ◽

Global Public Health ◽

Drug Usage ◽

Inappropriate Use ◽

Public Health Challenges ◽

Eskape Pathogens

The ESKAPE pathogens (Enterococcus faecium,Staphylococcus aureus,Klebsiella pneumoniae,Acinetobacter baumannii,Pseudomonas aeruginosa, andEnterobacterspecies) are the leading cause of nosocomial infections throughout the world. Most of them are multidrug resistant isolates, which is one of the greatest challenges in clinical practice. Multidrug resistance is amongst the top three threats to global public health and is usually caused by excessive drug usage or prescription, inappropriate use of antimicrobials, and substandard pharmaceuticals. Understanding the resistance mechanisms of these bacteria is crucial for the development of novel antimicrobial agents or other alternative tools to combat these public health challenges. Greater mechanistic understanding would also aid in the prediction of underlying or even unknown mechanisms of resistance, which could be applied to other emerging multidrug resistant pathogens. In this review, we summarize the known antimicrobial resistance mechanisms of ESKAPE pathogens.

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A Critical Evaluation of Newer β-Lactam Antibiotics for Treatment of Pseudomonas aeruginosa Infections

Annals of Pharmacotherapy ◽

10.1177/1060028020974003 ◽

2020 ◽

pp. 106002802097400

Author(s):

Kathleen C. Blomquist ◽

David E. Nix

Keyword(s):

Pseudomonas Aeruginosa ◽

Clinical Data ◽

Therapeutic Potential ◽

Data Extraction ◽

Relevant Literature ◽

Acquired Resistance ◽

Critical Evaluation ◽

Multidrug Resistant ◽

Resistance Mechanisms ◽

Study Selection

Objective: This article critically evaluates common Pseudomonas aeruginosa resistance mechanisms and the properties newer β-lactam antimicrobials possess to evade these mechanisms. Data Sources: An extensive PubMed, Google Scholar, and ClinicalTrials.gov search was conducted (January 1995 to July 2020) to identify relevant literature on epidemiology, resistance mechanisms, antipseudomonal agents, newer β-lactam agents, and clinical data available pertaining to P aeruginosa. Study Selection and Data Extraction: Relevant published articles and package inserts were reviewed for inclusion. Data Synthesis: Therapeutic options to treat P aeruginosa infections are limited because of its intrinsic and acquired resistance mechanisms. The goal was to identify advances with newer β-lactams and characterize improvements in therapeutic potential for P aeruginosa infections. Relevance to Patient Care and Clinical Practice: Multidrug-resistant (MDR) P aeruginosa isolates are increasingly encountered from a variety of infections. This review highlights potential activity gains of newer β-lactam antibacterial drugs and the current clinical data to support their use. Pharmacists will be asked to recommend or evaluate the use of these agents and need to be aware of information specific to P aeruginosa, which differs from experience derived from Enterobacterales infections. Conclusions: Newer agents, including ceftazidime-avibactam, ceftolozane-tazobactam, imipenem-relebactam, and cefiderocol, are useful for the treatment of MDR P aeruginosa infections. These agents offer improved efficacy and less toxicity compared with aminoglycosides and polymyxins and can be used for pathogens that are resistant to first-line antipseudomonal β-lactams. Selection of one agent over another should consider availability, turnaround of susceptibility testing, and product cost. Efficacy data specific for pseudomonal infections are limited, and there are no direct comparisons between the newer agents.

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Rational Design of Engineered Cationic Antimicrobial Peptides Consisting Exclusively of Arginine and Tryptophan, and Their Activity against Multidrug-Resistant Pathogens

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02218-12 ◽

2013 ◽

Vol 57 (6) ◽

pp. 2511-2521 ◽

Cited By ~ 83

Author(s):

Berthony Deslouches ◽

Jonathan D. Steckbeck ◽

Jodi K. Craigo ◽

Yohei Doi ◽

Timothy A. Mietzner ◽

...

Keyword(s):

Antimicrobial Peptides ◽

Rational Design ◽

Antimicrobial Agents ◽

Divalent Cations ◽

Multidrug Resistant ◽

Resistance Mechanisms ◽

Broth Culture ◽

Cationic Antimicrobial Peptides ◽

Content Type ◽

Amphipathic Helices

ABSTRACTThe emergence of multidrug-resistant (MDR) pathogens underscores the need for new antimicrobial agents to overcome the resistance mechanisms of these organisms. Cationic antimicrobial peptides (CAPs) provide a potential source of new antimicrobial therapeutics. We previously characterized a lytic base unit (LBU) series of engineered CAPs (eCAPs) of 12 to 48 residues demonstrating maximum antibacterial selectivity at 24 residues. Further, Trp substitution in LBU sequences increased activity against bothP. aeruginosaandS. aureusunder challenging conditions (e.g., saline, divalent cations, and serum). Based on these findings, we hypothesized that the optimal length and, therefore, the cost for maximum eCAP activity under physiologically relevant conditions could be significantly reduced using only Arg and Trp arranged to form idealized amphipathic helices. Hence, we developed a novel peptide series, composed only of Arg and Trp, in a sequence predicted and verified by circular dichroism to fold into optimized amphipathic helices. The most effective antimicrobial activity was achieved at 12 residues in length (WR12) against a panel of both Gram-negative and Gram-positive clinical isolates, including extensively drug-resistant strains, in saline and broth culture and at various pH values. The results demonstrate that the rational design of CAPs can lead to a significant reduction in the length and the number of amino acids used in peptide design to achieve optimal potency and selectivity against specific pathogens.

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Clonal transmission and new mechanism of resistance to trimethoprim-sulfamethoxazole in Stenotrophomonas maltophilia strains isolated in a neonatology unit at Antananarivo, Madagascar, deciphered by whole genome sequence analysis

10.1101/696765 ◽

2019 ◽

Author(s):

Mamitina Alain Noah Rabenandrasana ◽

Volasoa Andrianoelina ◽

Melanie Bonneault ◽

Perlinot Herindrainy ◽

Benoit Garin ◽

...

Keyword(s):

Stenotrophomonas Maltophilia ◽

Antimicrobial Agents ◽

Susceptibility Testing ◽

Acquired Resistance ◽

Multidrug Resistant ◽

Resistance Mechanisms ◽

Whole Genome Sequence ◽

Resistant Organism ◽

Whole Genome ◽

Single Nucleotide

ABSTRACTStenotrophomonas maltophilia has been recognized as an emerging multidrug resistant organism in hospital settings due to its resistance to a broad range of antimicrobial agents. These include β-lactams and aminoglycosides, afforded by the existence of intrinsic and acquired resistance mechanisms. Trimethoprim/sulfamethoxazole (SXT) is recommended as one of the best treatment choices against S. maltophilia infections; however increasing resistance to SXT has complicated the treatment. From July 2014 to March 2015, individuals and surfaces from a neonatology ward in Antananarivo, Madagascar, were longitudinally followed to assess the transmission of bacteria resistant to antibiotics between neonates, individuals (parents and nurses) and ward environments. Four S. maltophilia strains were successively isolated from a water-tap (N=1), from feces obtained from a newborn (N=1), and nursing staff (N=2). Antimicrobial susceptibility testing and whole genome sequencing were performed on each isolate. Based on coregenome alignment, all strains were identical and belonged to the new sequence type ST-288. They were resistant to trimethoprim-sulfamethoxazole, carbapenems and intermediate to levofloxacin. Each isolate carried the aadB, strA, strB and sul1 genes located in a class I integron but variants of the dfrA gene were absent. We assessed by PROVEAN analysis the single nucleotide mutations found in folA, folC and folM genes and only the mutation in folA (A114T:GCC→ACC) has an effect on the activity of trimethoprim. Our findings demonstrated the prolonged presence of SXT-resistant S. maltophilia in a clinical setting with consecutive transfers from the environment to a newborn and staff based on the isolation dates. We also hypothesized that single nucleotide mutations in folA could be responsible for trimethoprim resistance.

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Nanotechnology in Modern Photodynamic Therapy of Cancer: A Review of Cellular Resistance Patterns Affecting the Therapeutic Response

Pharmaceutics ◽

10.3390/pharmaceutics12070632 ◽

2020 ◽

Vol 12 (7) ◽

pp. 632 ◽

Cited By ~ 2

Author(s):

Elvin Peter Chizenga ◽

Heidi Abrahamse

Keyword(s):

Photodynamic Therapy ◽

Therapeutic Response ◽

Therapeutic Option ◽

Acquired Resistance ◽

Resistance Mechanisms ◽

Minimal Risk ◽

Cancer Resistance ◽

Cellular Resistance ◽

Photodynamic Therapy Of Cancer ◽

Resistance Patterns

Photodynamic therapy (PDT) has emerged as a potential therapeutic option for most localized cancers. Its high measure of specificity and minimal risk of side effects compared to other therapies has put PDT on the forefront of cancer research in the current era. The primary cause of treatment failure and high mortality rates is the occurrence of cancer resistance to therapy. Hence, PDT is designed to be selective and tumor-specific. However, because of complex biological characteristics and cell signaling, cancer cells have shown a propensity to acquire cellular resistance to PDT by modulating the photosensitization process or its products. Fortunately, nanotechnology has provided many answers in biomedical and clinical applications, and modern PDT now employs the use of nanomaterials to enhance its efficacy and mitigate the effects of acquired resistance. This review, therefore, sought to scrutinize the mechanisms of cellular resistance that affect the therapeutic response with an emphasis on the use of nanomaterials as a way of overriding cancer cell resistance. The resistance mechanisms that have been reported are complex and photosensitizer (PS)-specific. We conclude that altering the structure of PSs using nanotechnology is an ideal paradigm for enhancing PDT efficacy in the presence of cellular resistance.

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The Action of Efflux Pump Genes in Conferring Drug Resistance to Klebsiella Species and Their Inhibition

Journal of Health and Allied Sciences NU ◽

10.1055/s-0041-1731914 ◽

2021 ◽

Author(s):

Priyanka Ashwath ◽

Akhila Dharnappa Sannejal

Keyword(s):

Drug Resistance ◽

Antimicrobial Agents ◽

Efflux Pump ◽

Acquired Resistance ◽

Efflux Pumps ◽

Multidrug Resistant ◽

Resistance Mechanisms ◽

Klebsiella Species ◽

Gram Negative ◽

Multidrug Efflux Pumps

AbstractNosocomial infections caused by Klebsiella species are characterized by high rates of morbidity and mortality. The emergence of the multidrug-resistant (MDR) and extensive drug-resistant (XDR) Gram-negative bacteria reduces the antibiotic efficacy in the treatment of infections caused by the microorganisms. Management of these infections is often difficult, due to the high frequency of strains resistant to multiple antimicrobial agents. Multidrug efflux pumps play a major role as a mechanism of antimicrobial resistance in Gram-negative pathogens. Efflux systems are significant in conferring intrinsic and acquired resistance to the bacteria. The emergence of increasing drug resistance among Klebsiella pneumoniae nosocomial isolates has limited the therapeutic options for treatment of these infections and hence there is a constant quest for an alternative. In this review, we discuss various resistance mechanisms, focusing on efflux pumps and related genes in conferring resistance to Klebsiella. The role of various efflux pump inhibitors (EPIs) in restoring the antibacterial activity has also been discussed. In specific, antisense oligonucleotides as alternative therapeutics in combatting efflux-mediated resistance in Klebsiella species have focused upon.

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Prevalence, Risk Factors, and Molecular Epidemiology of Intestinal Carbapenem-Resistant Pseudomonas aeruginosa

Microbiology Spectrum ◽

10.1128/spectrum.01344-21 ◽

2021 ◽

Author(s):

Yanyan Hu ◽

Yan Qing ◽

Jiawei Chen ◽

Congcong Liu ◽

Jiayue Lu ◽

...

Keyword(s):

Risk Factors ◽

Pseudomonas Aeruginosa ◽

Gastrointestinal Tract ◽

Resistance Genes ◽

Acquired Resistance ◽

Multidrug Resistant ◽

Resistance Mechanisms ◽

Human Gastrointestinal Tract ◽

Content Type ◽

Carbapenem Resistant

Pseudomonas aeruginosa may become multidrug-resistant (MDR) due to multiple inherited and acquired resistance mechanisms. The human gastrointestinal tract is known as a reservoir of P. aeruginosa and its resistance genes.

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Differences in fosfomycin resistance mechanisms between Pseudomonas aeruginosa and Enterobacterales

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01446-21 ◽

2021 ◽

Author(s):

Dina Zheng ◽

Phillip J. Bergen ◽

Cornelia B. Landersdorfer ◽

Elizabeth B. Hirsch

Keyword(s):

Pseudomonas Aeruginosa ◽

Acquired Resistance ◽

Drug Approval ◽

Multidrug Resistant ◽

Resistance Mechanisms ◽

Supporting Evidence ◽

E Coli ◽

Fosfomycin Resistance ◽

The 1960S ◽

Tract Infections

Multidrug-resistant (MDR) Pseudomonas aeruginosa presents a serious threat to public health due to its widespread resistance to numerous antibiotics. P. aeruginosa commonly causes nosocomial infections including urinary tract infections (UTI) which have become increasingly difficult to treat. The lack of effective therapeutic agents has renewed interest in fosfomycin, an old drug discovered in the 1960s and approved prior to the rigorous standards now required for drug approval. Fosfomycin has a unique structure and mechanism of action, making it a favorable therapeutic alternative for MDR pathogens that are resistant to other classes of antibiotics. The absence of susceptibility breakpoints for fosfomycin against P. aeruginosa limits its clinical use and interpretation due to extrapolation of breakpoints established for Escherichia coli or Enterobacterales without supporting evidence. Furthermore, fosfomycin use and efficacy for treatment of P. aeruginosa is also limited by both inherent and acquired resistance mechanisms. This narrative review provides an update on currently identified resistance mechanisms to fosfomycin, with a focus on those mediated by P. aeruginosa such as peptidoglycan recycling enzymes, chromosomal Fos enzymes, and transporter mutation. Additional fosfomycin resistance mechanisms exhibited by Enterobacterales including mutations in transporters and associated regulators, plasmid mediated Fos enzymes, kinases, and murA modification, are also summarized and contrasted. These data highlight that different fosfomycin resistance mechanisms may be associated with elevated MIC values in P. aeruginosa compared to Enterobacterales, emphasizing that extrapolation of E. coli breakpoints to P. aeruginosa should be avoided.

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616. Evaluation of In Vitro Susceptibility to Ceftazidime/Avibactam of Clinical Isolates of Carbapenem Nonsusceptible Gram-Negative Bacilli from Colombia

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.684 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S287-S287

Author(s):

Tobias M Appel ◽

Maria F Mojica ◽

Elsa De La Cadena ◽

Christian Pallares ◽

Maria Virginia Villegas

Keyword(s):

Therapeutic Option ◽

Generation Cephalosporin ◽

Multidrug Resistant ◽

Resistance Mechanisms ◽

Clinical Isolates ◽

In Vitro Susceptibility ◽

Gram Negative ◽

Fixed Concentration ◽

Class B

Abstract Background Ceftazidime/avibactam (CZA) is a combination of a third-generation cephalosporin and a diazabicyclooctane β-lactamase inhibitor, which is active against a broad range of class A, C and D β-lactamases. In Colombia, high rates of multidrug-resistant Enterobacteriaceae (Ent)and P. aeruginosa (Pae) have been reported. Of special concern are KPC enzymes endemic in Ent and found in Pae, which are associated with higher mortality and healthcare costs, as well as limited therapeutic options. Herein, we evaluate the susceptibility of clinical isolates of carbapenem nonsusceptible Ent (CNS-E) and Pae (CNS-P) to CZA with the aim of understanding its role as a therapeutic option for these bacteria. Methods Three hundred ninety-nine nonduplicate clinical isolates of carbapenem nonsusceptible Gram-negative bacilli were collected in 13 medical centers from 12 Colombian cities, from January 2016 to October 2017 (137 K. pneumoniae [Kpn], 76 E. coli, 34 Enterobacter spp., 21 S. marcescens [Sma] and 131 Pae). CNS-E was defined as minimum inhibitory concentrations (MIC) ≥1 mg/L for ertapenem and CNS-P was defined as MIC ≥4 mg/L for meropenem. MIC were determined by broth microdilution and interpreted according to current CLSI guidelines. CZA MIC were determined using double dilutions of ceftazidime and a fixed concentration of avibactam of 4 mg/L. Comparator agents were ceftazidime, cefepime, piperacillin/tazobactam, imipenem, meropenem, tigecycline (TGC), and fosfomycin (FOS). Results Antimicrobial activity of CZA and comparators is shown in Table 1. CZA susceptibility ranged from 69% in Kpn to 81% in Sma, whereas 49% of CNS-P were susceptible to CZA. In both, CNS-E and CNS-P, CZA was superior to all other tested β-lactam compounds. Notably, in CNS-E CZA susceptibility was comparable to FOS and TGC (except for TGC in Sma). Conclusion CZA is the most active β-lactam against CNS-E and CNS-P. CZA nonsusceptibility suggests the presence of other resistance mechanisms, such as class B β-lactamases that are not inhibited by avibactam, and which are more frequently reported in CNS-P. Our results highlight the key role of new agents such as CZA in KPC endemic countries and the need for surveillance studies to determine the nature of resistance mechanisms. Disclosures All authors: No reported disclosures.

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Microbicides Alter the Expression and Function of RND-Type Efflux Pump AdeABC in Biofilm-Associated Cells of Acinetobacter baumannii Clinical Isolates

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01045-15 ◽

2015 ◽

Vol 60 (1) ◽

pp. 57-63 ◽

Cited By ~ 12

Author(s):

Suvarna Krishnamoorthy ◽

Bhavikkumar P. Shah ◽

Hiu Ham Lee ◽

Luis R. Martinez

Keyword(s):

Acinetobacter Baumannii ◽

Biofilm Formation ◽

Efflux Pump ◽

Acquired Resistance ◽

Multidrug Resistant ◽

Clinical Isolates ◽

Content Type ◽

Abiotic Surfaces ◽

Hospital Environments ◽

And Function

ABSTRACTAcinetobacter baumanniiis a Gram-negative bacterium that causes nosocomial infections worldwide. This microbe's propensity to form biofilms allows it to persist and to survive on clinical abiotic surfaces for long periods. In fact,A. baumanniibiofilm formation and its multidrug-resistant nature severely compromise our capacity to care for patients in hospital environments. In contrast, microbicides such as cetrimide (CT) and chlorhexidine (CHX) play important roles in the prevention and treatment of infections. We assessed the efficacy of CT and CHX, either alone or in combination, in eradicatingA. baumanniibiofilms formed by clinical isolates, by using stainless steel washers to mimic hard abiotic surfaces found in hospital settings. We demonstrated that increasing amounts of each microbicide, alone or in combination, were able to damage and to reduce the viability ofA. baumanniibiofilms efficaciously. Interestingly, theadeBgene of the resistance-nodulation-cell division (RND) family is predominantly associated with acquired resistance to antimicrobials inA. baumannii. We showed that CT and CHX adversely modified the expression and function of the RND-type efflux pump AdeABC in biofilm-associatedA. baumanniicells. Furthermore, we established that these microbicides decreased the negative charges onA. baumanniicell membranes, causing dysregulation of the efflux pump and leading to cell death. Our findings suggest that CT and CHX, alone or in combination, can be used efficaciously for eradication ofA. baumanniifrom hospital surfaces, in order to reduce infections caused by this nosocomial agent.

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