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

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.

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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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Post-Covid-19 Era: What is Next?

10.5772/intechopen.96276 ◽

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.

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Resistance to nitrofurantoin is an indicator of extensive drug-resistant (XDR) Enterobacteriaceae

Journal of Medical Microbiology ◽

10.1099/jmm.0.001347 ◽

2021 ◽

Vol 70 (4) ◽

Author(s):

Balaram Khamari ◽

Prakash Kumar ◽

Bulagonda Eswarappa Pradeep

Keyword(s):

Antimicrobial Agents ◽

Efflux Pump ◽

Treatment Options ◽

Strong Association ◽

Multidrug Resistant ◽

Resistance Mechanisms ◽

Resistant Bacteria ◽

Drug Resistant ◽

Content Type ◽

Link Type

Introduction. Nitrofurantoin is one of the preferred antibiotics in the treatment of uropathogenic multidrug-resistant (MDR) infections. However, resistance to nitrofurantoin in extensively drug-resistant (XDR) bacteria has severely limited the treatment options. Gap statement. Information related to co-resistance or collateral sensitivity (CS) with reference to nitrofurantoin resistant bacteria is limited. Aim. To study the potential of nitrofurantoin resistance as an indicator of the XDR phenotype in Enterobacteriaceae . Methods. One hundred (45 nitrofurantoin-resistant, 21 intermediately resistant and 34 nitrofurantoin-susceptible) Enterobacteriaceae were analysed in this study. Antibiotic susceptibility testing (AST) against nitrofurantoin and 17 other antimicrobial agents across eight different classes was performed by using the Vitek 2.0 system. The isolates were screened for the prevalence of acquired antimicrobial resistance (AMR) and efflux pump genes by PCR. Results. In total, 51 % of nitrofurantoin-resistant and 28 % of intermediately nitrofurantoin resistant isolates exhibited XDR characteristics, while only 3 % of nitrofurantoin-sensitive isolates were XDR (P=0.0001). Significant co-resistance was observed between nitrofurantoin and other tested antibiotics (β-lactam, cephalosporin, carbapenem, aminoglycoside and tetracycline). Further, the prevalence of AMR and efflux pump genes was higher in the nitrofurantoin-resistant strains compared to the susceptible isolates. A strong association was observed between nitrofurantoin resistance and the presence of bla PER-1, bla NDM-1, bla OXA-48, ant(2) and oqxA-oqxB genes. Tigecycline (84 %) and colistin (95 %) were the only antibiotics to which the majority of the isolates were susceptible. Conclusion. Nitrofurantoin resistance could be an indicator of the XDR phenotype among Enterobacteriaceae , harbouring multiple AMR and efflux pump genes. Tigecycline and colistin are the only antibiotics that could be used in the treatment of such XDR infections. A deeper understanding of the co-resistance mechanisms in XDR pathogens and prescription of AST-based appropriate combination therapy may help mitigate this problem.

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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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QSAR Studies on Bacterial Efflux Pump Inhibitors

Quantitative Structure-Activity Relationships in Drug Design, Predictive Toxicology, and Risk Assessment - Advances in Chemical and Materials Engineering ◽

10.4018/978-1-4666-8136-1.ch007 ◽

2015 ◽

pp. 238-268 ◽

Cited By ~ 1

Author(s):

Khac-Minh Thai ◽

Trong-Nhat Do ◽

Thuy-Viet-Phuong Nguyen ◽

Duc-Khanh-Tho. Nguyen ◽

Thanh-Dao Tran

Keyword(s):

Bacterial Resistance ◽

Efflux Pump ◽

Current Knowledge ◽

Efflux Pumps ◽

Quantitative Structure Activity Relationship ◽

Antimicrobial Drug Resistance ◽

Qsar Studies ◽

Hospital Stays ◽

Efflux Pump Inhibitors

Antimicrobial drug resistance occurs when bacteria undergo certain modifications to eliminate the effectiveness of drugs, chemicals, or other agents designed to cure infections. To date, the burden of resistance has remained one of the major clinical concerns as it renders prolonged and complicated treatments, thereby increasing the medical costs with lengthier hospital stays. Of complex causes for bacterial resistance, there has been increasing evidence that proved the significant role of efflux pumps in antibiotic resistance. Coadministration of Efflux Pump Inhibitors (EPIs) with antibiotics has been considered one of the promising ways not only to improve the efficacy but also to extend the clinical utility of existing antibiotics. This chapter begins with outlining current knowledge about bacterial efflux pumps and drug designs applied in identification of their modulating compounds. Following, the chapter addresses and provides a discussion on Quantitative Structure-Activity Relationship (QSAR) analyses in search of novel and potent efflux pump inhibitors.

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An alkylaminoquinazoline restores antibiotic activity in Gram-negative resistant isolates

Microbiology ◽

10.1099/mic.0.045716-0 ◽

2011 ◽

Vol 157 (2) ◽

pp. 566-571 ◽

Cited By ~ 17

Author(s):

Abdallah Mahamoud ◽

Jacqueline Chevalier ◽

Milad Baitiche ◽

Elissavet Adam ◽

Jean-Marie Pagès

Keyword(s):

Efflux Pump ◽

Bacterial Species ◽

Efflux Pumps ◽

Multidrug Resistant ◽

Side Chain ◽

Structural Class ◽

Gram Negative ◽

Activity Spectrum ◽

Efflux Pump Inhibitors ◽

Drug Efflux Pump

To date, various bacterial drug efflux pump inhibitors (EPIs) have been described. They exhibit variability in their activity spectrum with respect to antibiotic structural class and bacterial species. Among the various 4-alkylaminoquinazoline derivatives synthesized and studied in this work, one molecule, 1167, increased the susceptibility of important human-pathogenic, resistant, Gram-negative bacteria towards different antibiotic classes. This 4-(3-morpholinopropylamino)-quinazoline induced an increase in the activity of chloramphenicol, nalidixic acid, norfloxacin and sparfloxacin, which are substrates of the AcrAB-TolC and MexAB-OprM efflux pumps that act in these multidrug-resistant isolates. In addition, 1167 increased the intracellular concentration of chloramphenicol in efflux pump-overproducing strains. The rate of restoration depended on the structure of the antibiotic, suggesting that different sites in the efflux pumps may be involved. A molecule exhibiting a morpholine functional group and a propyl extension of the side chain was more active.

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Microbial Efflux Pump Inhibitors: A Journey around Quinoline and Indole Derivatives

Molecules ◽

10.3390/molecules26226996 ◽

2021 ◽

Vol 26 (22) ◽

pp. 6996

Author(s):

Giada Cernicchi ◽

Tommaso Felicetti ◽

Stefano Sabatini

Keyword(s):

Efflux Pump ◽

Specific Resistance ◽

Resistance Mechanisms ◽

Future Research ◽

Indole Derivatives ◽

Great Opportunity ◽

Structure Activity ◽

New Antibiotics ◽

Efflux Pump Inhibitors ◽

Inhibitory Drug

Antimicrobial resistance (AMR) is a complex threat to human health and, to date, it represents a hot topic in drug discovery. The use of non-antibiotic molecules to block resistance mechanisms is a powerful alternative to the identification of new antibiotics. Bacterial efflux pumps exert the early step of AMR development, allowing the bacteria to grow in presence of sub-inhibitory drug concentration and develop more specific resistance mechanisms. Thus, efflux pump inhibitors (EPIs) offer a great opportunity to fight AMR, potentially restoring antibiotic activity. Based on our experience in designing and synthesizing novel EPIs, herein, we retrieved information around quinoline and indole derivatives reported in literature on this topic. Thus, our aim was to collect all data around these promising classes of EPIs in order to delineate a comprehensive structure–activity relationship (SAR) around each core for different microbes. With this review article, we aim to help future research in the field in the discovery of new microbial EPIs with improved activity and a better safety profile.

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

10.20944/preprints201910.0255.v1 ◽

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.

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Berberine reverses multidrug resistance in Candida albicans by hijacking the drug efflux pump Mdr1p

10.1101/2020.06.26.173484 ◽

2020 ◽

Author(s):

Yaojun Tong ◽

Nuo Sun ◽

Xiangming Wang ◽

Qi Wei ◽

Yu Zhang ◽

...

Keyword(s):

Candida Albicans ◽

Multidrug Resistance ◽

Efflux Pump ◽

Efflux Pumps ◽

Multidrug Resistant ◽

Major Facilitator Superfamily ◽

Drug Efflux ◽

Multidrug Efflux Pump ◽

Drug Efflux Pumps ◽

Major Facilitator

AbstractClinical use of antimicrobials faces great challenges from the emergence of multidrug resistant (MDR) pathogens. The overexpression of drug efflux pumps is one of the major contributors to MDR. It is considered as a promising approach to overcome MDR by reversing the function of drug efflux pumps. In the life-threatening fungal pathogen Candida albicans, the major facilitator superfamily (MFS) transporter Mdr1p can excrete many structurally unrelated antifungals, leading to multidrug resistance. Here we report a counterintuitive case of reversing multidrug resistance in C. albicans by using a natural product berberine to hijack the overexpressed Mdr1p for its own importation. Moreover, we illustrate that the imported berberine accumulates in mitochondria, and compromises the mitochondrial function by impairing mitochondrial membrane potential and mitochondrial Complex I. It results in the selective elimination of Mdr1p overexpressed C. albicans cells. Furthermore, we show that berberine treatment can prolong the mean survival time (MST) of mice with a blood-borne dissemination of Mdr1p overexpressed multidrug resistant candidiasis. This study provided a potential direction of novel anti-MDR drug discovery by screening for multidrug efflux pump converters.

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

Antibiotics ◽

10.3390/antibiotics8040229 ◽

2019 ◽

Vol 8 (4) ◽

pp. 229 ◽

Cited By ~ 8

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.

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