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

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

Antibiotics ◽

10.3390/antibiotics10121502 ◽

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.

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Quinazolinone Fungal Efflux Pump Inhibitors. Part 2. In vitro Structure?Activity Relationships of (N-Methyl-piperazinyl)-Containing Derivatives.

ChemInform ◽

10.1002/chin.200503155 ◽

2005 ◽

Vol 36 (3) ◽

Author(s):

William J. Watkins ◽

et al. et al.

Keyword(s):

Efflux Pump ◽

Structure Activity Relationships ◽

Structure Activity ◽

Efflux Pump Inhibitors

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Quantitative structure activity relationship (QSAR) of piperine analogsfor bacterial NorA efflux pump inhibitors

European Journal of Medicinal Chemistry ◽

10.1016/j.ejmech.2009.05.004 ◽

2009 ◽

Vol 44 (10) ◽

pp. 4128-4135 ◽

Cited By ~ 25

Author(s):

Amit Nargotra ◽

Sujata Sharma ◽

Jawahir Lal Koul ◽

Pyare Lal Sangwan ◽

Inshad Ali Khan ◽

...

Keyword(s):

Efflux Pump ◽

Quantitative Structure Activity Relationship ◽

Structure Activity Relationship ◽

Activity Relationship ◽

Quantitative Structure ◽

Structure Activity ◽

Efflux Pump Inhibitors

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Quinazolinone fungal efflux pump inhibitors. Part 2: In vitro structure–activity relationships of (N-methyl-piperazinyl)-containing derivatives

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/j.bmcl.2004.07.071 ◽

2004 ◽

Vol 14 (20) ◽

pp. 5133-5137 ◽

Cited By ~ 10

Author(s):

William J. Watkins ◽

Rémy C. Lemoine ◽

Lee Chong ◽

Aesop Cho ◽

Thomas E. Renau ◽

...

Keyword(s):

Efflux Pump ◽

Structure Activity Relationships ◽

Structure Activity ◽

Efflux Pump Inhibitors

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Antimicrobial Adjuvants - A Novel Approach to Manage Antimicrobial Resistance

Anti-Infective Agents ◽

10.2174/2211352518666200224093739 ◽

2021 ◽

Vol 18 (4) ◽

pp. 315-325

Author(s):

Chirag Patel ◽

Sanjeev Acharya ◽

Priyanka Patel

Keyword(s):

Antibiotic Resistance ◽

Efflux Pump ◽

Health Issues ◽

Promising Strategy ◽

Novel Approach ◽

New Antibiotics ◽

Efflux Pump Inhibitors ◽

Emergence Of Resistance ◽

Permeability Enhancers

Antibiotic resistance is one of the most prevalent, complex and serious global health issues, and needs to be monitored and controlled with medicine. Many approaches have been used to reduce the emergence and impact of resistance to antibiotics. The antimicrobial adjuvant approach is considered as novel, more effective and less expensive. The said approach not only suppresses the emergence of resistance but also conserves the activity of existing antibiotics by offering a promising strategy that is also complementary to the discovery of new antibiotics. This review contains an outline of the basic types of antibiotic adjuvant, their structure, the basis of their operation, their substrate antibiotics and the challenges in this field, as well as the role of potential compounds, namely β-lactamase inhibitors, efflux pump inhibitors and permeability enhancers in antibiotic resistance and their possible solutions.

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Quantitative structure–activity relationship (QSAR) of aryl alkenyl amides/imines for bacterial efflux pump inhibitors

European Journal of Medicinal Chemistry ◽

10.1016/j.ejmech.2008.02.015 ◽

2009 ◽

Vol 44 (1) ◽

pp. 229-238 ◽

Cited By ~ 24

Author(s):

A. Nargotra ◽

S. Koul ◽

S. Sharma ◽

I.A. Khan ◽

A. Kumar ◽

...

Keyword(s):

Efflux Pump ◽

Quantitative Structure Activity Relationship ◽

Structure Activity Relationship ◽

Activity Relationship ◽

Quantitative Structure ◽

Structure Activity ◽

Efflux Pump Inhibitors

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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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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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