scholarly journals Effectiveness of Efflux Pump Inhibitors as Biofilm Disruptors and Resistance Breakers in Gram-Negative (ESKAPEE) Bacteria

Antibiotics ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 229 ◽  
Author(s):  
Akif Reza ◽  
J. Mark Sutton ◽  
Khondaker Miraz Rahman
Keyword(s):  
Antibiotic Resistance ◽  
Antimicrobial Resistance ◽  
Efflux Pump ◽  
Protein Structures ◽  
Underlying Mechanism ◽  
Resistance Mechanisms ◽  
Healthcare Provision ◽  
Gram Negative ◽  
Environmental Threats ◽  
Efflux Pump Inhibitors

Antibiotic resistance represents a significant threat to the modern healthcare provision. The ESKAPEE pathogens (Enterococcus faecium., Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp. and Escherichia coli), in particular, have proven to be especially challenging to treat, due to their intrinsic and acquired ability to rapidly develop resistance mechanisms in response to environmental threats. The development of biofilm has been characterised as an essential contributing factor towards antimicrobial-resistance and tolerance. Several studies have implicated the involvement of efflux pumps in antibiotic resistance, both directly, via drug extrusion and indirectly, through the formation of biofilm. As a result, the underlying mechanism of these pumps has attracted considerable interest due to the potential of targeting these protein structures and developing novel adjunct therapies. Subsequent investigations have revealed the ability of efflux pump-inhibitors (EPIs) to block drug-extrusion and disrupt biofilm formation, thereby, potentiating antibiotics and reversing resistance of pathogen towards them. This review will discuss the potential of EPIs as a possible solution to antimicrobial resistance, examining different challenges to the design of these compounds, with an emphasis on Gram-negative ESKAPEE pathogens.

scholarly journals Effectiveness of Efflux Pump Inhibitors as Biofilm Disruptors and Resistance Breakers in Gram-negative (ESKAPEE) Bacteria

2019 ◽  
Author(s):  
Akif Reza ◽  
J. Mark Sutton ◽  
Khondaker Miraz Rahman
Keyword(s):  
Antibiotic Resistance ◽  
Antimicrobial Resistance ◽  
Efflux Pump ◽  
Protein Structures ◽  
Underlying Mechanism ◽  
Resistance Mechanisms ◽  
Healthcare Provision ◽  
Gram Negative ◽  
Environmental Threats ◽  
Efflux Pump Inhibitors

Antibiotic resistance represents a significant threat to the modern healthcare provision. The ESKAPEE pathogens, in particular, have proven to be especially challenging to treat, due to their intrinsic and acquired ability to rapidly develop resistance mechanisms in response to environmental threats. The development of biofilm has been characterised as an essential contributing factor towards antimicrobial-resistance and tolerance. Several studies have implicated the involvement of efflux pumps in antibiotic resistance, both directly, via drug extrusion and indirectly, through the formation of biofilm. As a result, the underlying mechanism of these pumps has attracted considerable interest due to the potential of targeting these protein structures and developing novel adjunct therapies. Subsequent investigations have revealed the ability of efflux pump-inhibitors (EPIs) to block drug-extrusion and disrupt biofilm formation, thereby, potentiating antibiotics and reversing resistance of pathogen towards them. This review will discuss the potential of EPIs as a possible solution to antimicrobial resistance, examining different challenges to the design of these compounds, with an emphasis on Gram-negative ESKAPEE pathogens.

scholarly journals ToxR mediates the antivirulence activity of phenyl-arginine-β-naphthylamide to attenuate Vibrio cholerae virulence.

2021 ◽  
Author(s):  
Yuding Weng ◽  
Thomas F. Bina ◽  
X. Renee Bina ◽  
James E. Bina
Keyword(s):  
Antimicrobial Resistance ◽  
Vibrio Cholerae ◽  
Virulence Factor ◽  
Efflux Pump ◽  
Feedback Mechanism ◽  
Gram Negative ◽  
Factor Production ◽  
Regulatory Circuit ◽  
Efflux Pump Inhibitors ◽  
Virulence Factor Production

Multidrug efflux systems belonging to the resistance-nodulation-cell division (RND) family are ubiquitous in Gram negative bacteria and critical for antimicrobial resistance. This realization has led to efforts to develop efflux pump inhibitors (EPI) for use as adjuvants for antibiotic treatment of resistant organisms. However, the functions of RND transporters extend beyond antimicrobial resistance to include physiological functions that are critical for pathogenesis, suggesting that EPIs could also be used as antivirulence therapeutics. This was documented in the enteric pathogen Vibrio cholerae where EPIs were shown to attenuate the production of the critical virulence factors cholera toxin (CT) and the toxin coregulated pilus (TCP). In this study we investigated the antivirulence mechanism of action of the EPI phenyl-arginine-β-naphthylamide (PAβN) on V. cholerae. Using bioassays, we documented that PAβN inhibited virulence factor production in three epidemic V. cholerae isolates. Transcriptional reporter studies and mutant analysis indicated that PAβN initiated a ToxR-dependent regulatory circuit to activate leuO expression and that LeuO repressed the expression of the critical virulence activator aphA to attenuate CT and TCP production. The antivirulence activity of PAβN was found to be dependent on the ToxR periplasmic sensing domain suggesting that a feedback mechanism was involved in its activity. Collectively the data indicated that PAβN inhibited V. cholerae virulence factor production by activating a ToxR-dependent metabolic feedback mechanism to repress the expression of the ToxR virulence regulon. This suggests that efflux pump inhibitors could be used as antivirulence therapeutics for the treatment of cholera and perhaps other gram negative pathogens.

scholarly journals Efflux Pump Mediated Antimicrobial Resistance by Staphylococci in Health-Related Environments: Challenges and the Quest for Inhibition

Antibiotics ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1502
Author(s):  
Abolfazl Dashtbani-Roozbehani ◽  
Melissa H. Brown
Keyword(s):  
Antimicrobial Resistance ◽  
Antimicrobial Agents ◽  
Efflux Pump ◽  
Current Knowledge ◽  
Efflux Pumps ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Multidrug Efflux Pump ◽  
New Antibiotics ◽  
Efflux Pump Inhibitors

The increasing emergence of antimicrobial resistance in staphylococcal bacteria is a major health threat worldwide due to significant morbidity and mortality resulting from their associated hospital- or community-acquired infections. Dramatic decrease in the discovery of new antibiotics from the pharmaceutical industry coupled with increased use of sanitisers and disinfectants due to the ongoing COVID-19 pandemic can further aggravate the problem of antimicrobial resistance. Staphylococci utilise multiple mechanisms to circumvent the effects of antimicrobials. One of these resistance mechanisms is the export of antimicrobial agents through the activity of membrane-embedded multidrug efflux pump proteins. The use of efflux pump inhibitors in combination with currently approved antimicrobials is a promising strategy to potentiate their clinical efficacy against resistant strains of staphylococci, and simultaneously reduce the selection of resistant mutants. This review presents an overview of the current knowledge of staphylococcal efflux pumps, discusses their clinical impact, and summarises compounds found in the last decade from plant and synthetic origin that have the potential to be used as adjuvants to antibiotic therapy against multidrug resistant staphylococci. Critically, future high-resolution structures of staphylococcal efflux pumps could aid in design and development of safer, more target-specific and highly potent efflux pump inhibitors to progress into clinical use.

Success and Challenges Associated with Large Scale Collaborative Surveillance for Carbapenemase Genes in Gram Negative Bacteria

2021 ◽  
Author(s):  
Sanchita Das ◽  
Karen Bush
Keyword(s):  
Antibiotic Resistance ◽  
Antimicrobial Resistance ◽  
Large Scale ◽  
Resistance Mechanisms ◽  
Gram Negative Bacteria ◽  
Routine Laboratory ◽  
Significant Morbidity ◽  
Gram Negative ◽  
Surveillance Studies ◽  
The One

The emergence and spread of antimicrobial resistance, especially in Gram negative bacteria has led to significant morbidity and increased cost of healthcare. Large surveillance studies such as the one performed by the Antibiotic Resistance Laboratory Network are immensely valuable in understanding the scope of resistance mechanisms especially among carbapenemase producing Gram negative bacteria. However, the routine laboratory detection of carbapenemases in these bacteria remain challenging and require further optimization.

scholarly journals Post-Covid-19 Era: What is Next?

2021 ◽  
Author(s):  
Shiela Chetri
Keyword(s):  
Escherichia Coli ◽  
Antibiotic Resistance ◽  
Antimicrobial Resistance ◽  
Antimicrobial Agents ◽  
Efflux Pump ◽  
Carbapenem Resistance ◽  
Resistance Mechanisms ◽  
Multidrug Efflux Pump ◽  
High Risk Factors ◽  
Clinical Complications

Antimicrobial resistance (AMR) is a natural phenomenon in bacteria which becomes a threat for health-care settings around the world. A concerted global response is needed to tackle rising rates of antibiotic resistance, without it we risk returning to the pre antibiotic era. As bacteria evolve very fast according to the environment in which they inhabit via developing different defence mechanisms to combat with the noxious agents like different classes of antibiotics including carbapenems. This results into treatment failure and clinical complications. Global emergence of antibiotic resistance due to bacterial multidrug efflux pump systems are a major and common mechanism of intrinsic antimicrobial resistance employed by bacteria which are spreading rapidly due to over use or misuse of antimicrobial agents. This review mainly focusses on the transcriptional expression of efflux pump system AcrAB-TolC, local regulatory genes (AcrR and AcrS), mediating carbapenem resistance in clinical isolates of Escherichia coli under antibiotic stress, a genetic interplay study between intrinsic and acquired antibiotic resistance mechanisms along with a brief summary on high risk factors and prevalence of urinary tract infections by multidrug resistant Uropathogenic Escherichia coli.

scholarly journals Antimicrobials and Food-Related Stresses as Selective Factors for Antibiotic Resistance along the Farm to Fork Continuum

Antibiotics ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 671
Author(s):  
Federica Giacometti ◽  
Hesamaddin Shirzad-Aski ◽  
Susana Ferreira
Keyword(s):  
Antibiotic Resistance ◽  
Food Safety ◽  
Antimicrobial Resistance ◽  
Food Processing ◽  
Resistance Mechanisms ◽  
Human Environment ◽  
Real Risk ◽  
Cross Adaptation ◽  
Novel Approaches

Antimicrobial resistance (AMR) is a global problem and there has been growing concern associated with its widespread along the animal–human–environment interface. The farm-to-fork continuum was highlighted as a possible reservoir of AMR, and a hotspot for the emergence and spread of AMR. However, the extent of the role of non-antibiotic antimicrobials and other food-related stresses as selective factors is still in need of clarification. This review addresses the use of non-antibiotic stressors, such as antimicrobials, food-processing treatments, or even novel approaches to ensure food safety, as potential drivers for resistance to clinically relevant antibiotics. The co-selection and cross-adaptation events are covered, which may induce a decreased susceptibility of foodborne bacteria to antibiotics. Although the available studies address the complexity involved in these phenomena, further studies are needed to help better understand the real risk of using food-chain-related stressors, and possibly to allow the establishment of early warnings of potential resistance mechanisms.

scholarly journals Correlation between the Antibiotic Resistance Genes and Susceptibility to Antibiotics among the Carbapenem-Resistant Gram-Negative Pathogens

Antibiotics ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 255
Author(s):  
Salma M. Abdelaziz ◽  
Khaled M. Aboshanab ◽  
Ibrahim S. Yahia ◽  
Mahmoud A. Yassien ◽  
Nadia A. Hassouna
Keyword(s):  
Antibiotic Resistance ◽  
Resistance Genes ◽  
Efflux Pump ◽  
Antibiotic Resistance Genes ◽  
Multiple Drug ◽  
P Value ◽  
Multidrug Efflux ◽  
Multidrug Efflux Pump ◽  
Gram Negative ◽  
Carbapenem Resistant

In this study, the correlation between the antibiotic resistance genes and antibiotic susceptibility among the carbapenem-resistant Gram-negative pathogens (CRGNPs) recovered from patients diagnosed with acute pneumonia in Egypt was found. A total of 194 isolates including Klebsiella pneumoniae (89; 46%), Escherichia coli (47; 24%) and Pseudomonas aeruginosa (58; 30%) were recovered. Of these, 34 (18%) isolates were multiple drug resistant (MDR) and carbapenem resistant. For the K. pneumoniae MDR isolates (n = 22), blaNDM (14; 64%) was the most prevalent carbapenemase, followed by blaOXA-48 (11; 50%) and blaVIM (4; 18%). A significant association (p value < 0.05) was observed between the multidrug efflux pump (AcrA) and resistance to β-lactams and the aminoglycoside acetyl transferase gene (aac-6’-Ib) gene and resistance to ciprofloxacin, azithromycin and β-lactams (except for aztreonam). For P. aeruginosa, a significant association was noticed between the presence of the blaSHV gene and the multidrug efflux pump (MexA) and resistance to fluoroquinolones, amikacin, tobramycin, co-trimoxazole and β-lactams and between the aac-6’-Ib gene and resistance to aminoglycosides. All P. aeruginosa isolates (100%) harbored the MexAB-OprM multidrug efflux pump while 86% of the K. pneumoniae isolates harbored the AcrAB-TolC pump. Our results are of great medical importance for the guidance of healthcare practitioners for effective antibiotic prescription.

scholarly journals Biocidal Agents Used for Disinfection Can Enhance Antibiotic Resistance in Gram-Negative Species

Antibiotics ◽  
2018 ◽  
Vol 7 (4) ◽  
pp. 110 ◽  
Author(s):  
Günter Kampf
Keyword(s):  
Antibiotic Resistance ◽  
Efflux Pump ◽  
Health Benefit ◽  
Cross Resistance ◽  
Gram Negative ◽  
Medline Search ◽  
Resistance To Antibiotics ◽  
Didecyldimethylammonium Chloride ◽  
Healthcare Associated ◽  
Sublethal Concentrations

Biocidal agents used for disinfection are usually not suspected to enhance cross-resistance to antibiotics. The aim of this review was therefore to evaluate the effect of 13 biocidal agents at sublethal concentrations on antibiotic resistance in Gram-negative species. A medline search was performed for each biocidal agent on antibiotic tolerance, antibiotic resistance, horizontal gene transfer, and efflux pump. In cells adapted to benzalkonium chloride a new resistance was most frequently found to ampicillin (eight species), cefotaxime (six species), and sulfamethoxazole (three species), some of them with relevance for healthcare-associated infections such as Enterobacter cloacae or Escherichia coli. With chlorhexidine a new resistance was often found to ceftazidime, sulfamethoxazole and imipenem (eight species each) as well as cefotaxime and tetracycline (seven species each). Cross-resistance to antibiotics was also found with triclosan, octenidine, sodium hypochlorite, and didecyldimethylammonium chloride. No cross-resistance to antibiotics has been described after low level exposure to ethanol, propanol, peracetic acid, polyhexanide, povidone iodine, glutaraldehyde, and hydrogen peroxide. Taking into account that some biocidal agents used in disinfectants have no health benefit (e.g., in alcohol-based hand rubs) but may cause antibiotic resistance it is obvious to prefer products without them.

scholarly journals Rapid Detection of PBP2a in Staphylococci from Shortly Incubated Subcultures of Positive Blood Cultures by an Immunochromatographic Assay

2021 ◽  
Author(s):  
Natalia Kolesnik-Goldmann ◽  
Elias Bodendoerfer ◽  
Kim Röthlin ◽  
Sebastian Herren ◽  
Frank Imkamp ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Antimicrobial Resistance ◽  
Patient Care ◽  
Rapid Detection ◽  
Resistance Mechanisms ◽  
Blood Cultures ◽  
Immunochromatographic Assay ◽  
Economic Costs ◽  
Major Threat ◽  
Improving Patient Care

Antibiotic resistance poses a major threat to health and incurs high economic costs worldwide. Rapid detection of resistance mechanisms can contribute to improving patient care and preventing the dissemination of antimicrobial resistance.

Comparative evaluation of Assays for Broad Detection of Molecular Resistance Mechanisms in Enterobacterales Isolates

2021 ◽  
Author(s):  
J. N. Brazelton de Cardenas ◽  
C. D. Garner ◽  
Y Su ◽  
L Tang ◽  
R. T. Hayden
Keyword(s):  
Antibiotic Resistance ◽  
Rapid Evolution ◽  
Antibiotic Resistance Genes ◽  
Resistance Mechanisms ◽  
Beta Lactam ◽  
Accurate Identification ◽  
Gram Negative ◽  
Diagnostic Role ◽  
Clinically Significant ◽  
Third Generation Cephalosporins

Rapid detection of antimicrobial resistance in both surveillance and diagnostic settings is still a major challenge for the clinical lab, compounded by the rapid evolution of antibiotic resistance mechanisms. This study compares four methods for the broad detection of antibiotic resistance genes in Enterobacterales isolates: two multiplex PCR assays, (the Streck ARM-D® beta-lactamase kit and the OpGen Acuitas AMR Gene Panel u5.47 (research use only (RUO)), and one microarray assay (the Check-MDR CT103XL assay), with whole genome sequencing as a reference standard. A total of 65 Gram-negative bacterial isolates, from 56 patients, classified by phenotypic AST as showing resistance to beta-lactam antimicrobials (ESBL positive, resistance to third generation cephalosporins or carbapenems), were included in the study. Overall concordance between the molecular assays and sequencing was high. While all three assays had similar performance, the OpGen Acuitas AMR assay had the highest overall percent concordance with sequencing results. The primary differences between the assays tested were the number and diversity of targets, ranging from 9 for Streck to 34 for OpGen. This study shows that commercially available PCR-based assays can provide accurate identification of antimicrobial resistant loci in clinically significant Gram-negative bacteria. Further studies are needed to determine the clinical diagnostic role and potential benefit of such methods.

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