Antimicrobial Adjuvants - A Novel Approach to Manage Antimicrobial Resistance

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.

scholarly journals Medicinal Chemistry Updates on Bacterial Efflux Pump Modulators

2019 ◽  
Vol 25 (42) ◽  
pp. 6030-6069 ◽  
Author(s):  
Fernando Durães ◽  
Madalena Pinto ◽  
Emília Sousa
Keyword(s):  
Energy Source ◽  
Antibiotic Resistance ◽  
Efflux Pump ◽  
Efflux Pumps ◽  
The Other ◽  
Drug Uptake ◽  
Health Issues ◽  
Gram Positive ◽  
Gram Positive Bacteria ◽  
Efflux Pump Inhibitors

Antibiotic resistance is one of the most pressing health issues of our days. It can arise due to a multiplicity of factors, such as target modification, decrease in the drug uptake, changes in the metabolic pathways and activation of efflux pumps. The overexpression of efflux pumps is responsible for the extrusion of drugs, making antibiotic therapy fail, as the quantity of intracellular antibiotic is not enough to provide the desired therapeutic effect. Efflux pumps can be included in five families according to their composition, nature of substrates, energy source, and number of transmembrane spanning regions. The ABC superfamily is mainly found in Gram-positive bacteria, use ATP as an energy source, and only a limited number of ABC pumps confer multidrug resistance (MDR). On the other hand, the MFS family, most present in Gram-positive bacteria, and the RND family, characteristic of Gram-negative bacteria, are most associated with antibiotic resistance. A wide variety of inhibitors have been disclosed for both families, from either natural or synthetic sources, or even drugs that are currently in therapy for other diseases. The other two families are the SMR, which are the smallest drug efflux proteins known, and the MATE family, whose pumps can also resort to the sodium gradient as an energy source. In this review, it is intended to present a comprehensive review of the classes of efflux pump inhibitors from the various sources, highlighting their structure-activity relationships, which can be useful for medicinal chemists in the pursuit of novel efflux pump inhibitors.

scholarly journals Microbial Efflux Systems and Inhibitors: Approaches to Drug Discovery and the Challenge of Clinical Implementation

2013 ◽  
Vol 7 (1) ◽  
pp. 34-52 ◽  
Author(s):  
Christina Kourtesi ◽  
Anthony R Ball ◽  
Ying-Ying Huang ◽  
Sanjay M Jachak ◽  
D Mariano A Vera ◽  
...  
Keyword(s):  
Efflux Pump ◽  
Major Theme ◽  
Clinical Implementation ◽  
Multidrug Efflux ◽  
Efflux System ◽  
Development Path ◽  
Microbial Infections ◽  
Efflux Pump Inhibitors ◽  
Shed Light

Conventional antimicrobials are increasingly ineffective due to the emergence of multidrug-resistance among pathogenic microorganisms. The need to overcome these deficiencies has triggered exploration for novel and unconventional approaches to controlling microbial infections. Multidrug efflux systems (MES) have been a profound obstacle in the successful deployment of antimicrobials. The discovery of small molecule efflux system blockers has been an active and rapidly expanding research discipline. A major theme in this platform involves efflux pump inhibitors (EPIs) from natural sources. The discovery methodologies and the available number of natural EPI-chemotypes are increasing. Advances in our understanding of microbial physiology have shed light on a series of pathways and phenotypes where the role of efflux systems is pivotal. Complementing existing antimicrobial discovery platforms such as photodynamic therapy (PDT) with efflux inhibition is a subject under investigation. This core information is a stepping stone in the challenge of highlighting an effective drug development path for EPIs since the puzzle of clinical implementation remains unsolved. This review summarizes advances in the path of EPI discovery, discusses potential avenues of EPI implementation and development, and underlines the need for highly informative and comprehensive translational approaches.

QSAR Studies on Bacterial Efflux Pump Inhibitors

2015 ◽  
pp. 238-268 ◽  
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.

scholarly journals Efflux Pump Inhibitors against Nontuberculous Mycobacteria

2020 ◽  
Vol 21 (12) ◽  
pp. 4191
Author(s):  
Laura Rindi
Keyword(s):  
Drug Resistance ◽  
Efflux Pump ◽  
Nontuberculous Mycobacteria ◽  
Current Knowledge ◽  
New Drugs ◽  
Human Pathogens ◽  
Intracellular Accumulation ◽  
Promising Strategy ◽  
Combined Use ◽  
Efflux Pump Inhibitors

Over the last years, nontuberculous mycobacteria (NTM) have emerged as important human pathogens. Infections caused by NTM are often difficult to treat due to an intrinsic multidrug resistance for the presence of a lipid-rich outer membrane, thus encouraging an urgent need for the development of new drugs for the treatment of mycobacterial infections. Efflux pumps (EPs) are important elements that are involved in drug resistance by preventing intracellular accumulation of antibiotics. A promising strategy to decrease drug resistance is the inhibition of EP activity by EP inhibitors (EPIs), compounds that are able to increase the intracellular concentration of antimicrobials. Recently, attention has been focused on identifying EPIs in mycobacteria that could be used in combination with drugs. The aim of the present review is to provide an overview of the current knowledge on EPs and EPIs in NTM and also, the effect of potential EPIs as well as their combined use with antimycobacterial drugs in various NTM species are described.

scholarly journals Antibiotic Resistance in Pseudomonas aeruginosa Strains with Increased Mutation Frequency Due to Inactivation of the DNA Oxidative Repair System

2009 ◽  
Vol 53 (6) ◽  
pp. 2483-2491 ◽  
Author(s):  
L. F. Mandsberg ◽  
O. Ciofu ◽  
N. Kirkby ◽  
L. E. Christiansen ◽  
H. E. Poulsen ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antibiotic Resistance ◽  
Polymorphonuclear Leukocytes ◽  
Oxidative Dna Damage ◽  
Efflux Pump ◽  
Repair System ◽  
High Frequencies ◽  
Resistance To Antibiotics ◽  
Development Of Resistance

ABSTRACT The chronic Pseudomonas aeruginosa infection of the lungs of cystic fibrosis (CF) patients is characterized by the biofilm mode of growth and chronic inflammation dominated by polymorphonuclear leukocytes (PMNs). A high percentage of P. aeruginosa strains show high frequencies of mutations (hypermutators [HP]). P. aeruginosa is exposed to oxygen radicals, both those generated by its own metabolism and especially those released by a large number of PMNs in response to the chronic CF lung infection. Our work therefore focused on the role of the DNA oxidative repair system in the development of HP and antibiotic resistance. We have constructed and characterized mutT, mutY, and mutM mutants in P. aeruginosa strain PAO1. The mutT and mutY mutants showed 28- and 7.5-fold increases in mutation frequencies, respectively, over that for PAO1. These mutators had more oxidative DNA damage (higher levels of 7,8-dihydro-8-oxodeoxyguanosine) than PAO1 after exposure to PMNs, and they developed resistance to antibiotics more frequently. The mechanisms of resistance were increased β-lactamase production and overexpression of the MexCD-OprJ efflux-pump. Mutations in either the mutT or the mutY gene were found in resistant HP clinical isolates from patients with CF, and complementation with wild-type genes reverted the phenotype. In conclusion, oxidative stress might be involved in the development of resistance to antibiotics. We therefore suggest the possible use of antioxidants for CF patients to prevent the development of antibiotic resistance.

scholarly journals Role of efflux pump inhibitor in decreasing antibiotic cross-resistance of Pseudomonas aeruginosa in a burn hospital in Iran

2016 ◽  
Vol 10 (06) ◽  
pp. 600-604 ◽  
Author(s):  
Mahshid Talebi-Taher ◽  
َAli Majidpour ◽  
Abbas Gholami ◽  
Samira Rasouli-Kouhi ◽  
Maryam Adabi
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Efflux Pump ◽  
Efflux Pumps ◽  
Disk Diffusion ◽  
Diffusion Method ◽  
Cross Resistance ◽  
Beta Lactams ◽  
Efflux Pump Inhibitor ◽  
Efflux Pump Inhibitors

Introduction: Multidrug resistance in Pseudomonas aeruginosa may be due to efflux pump overexpression. This study phenotypically examined the role of efflux pump inhibitors in decreasing antibiotic cross-resistance between beta-lactams, fluoroquinolones, and aminoglycosides in P. aeruginosa isolates from burn patients in Iran. Methodology: A total of 91 phenotypically and genotypically confirmed P. aeruginosa samples were studied. Multidrug cross-resistance was determined using the disk diffusion method and minimum inhibitory concentration (MIC) test. The contribution of efflux pumps was determined by investigating MIC reduction assay to markers of beta-lactams, fluoroquinolones, and aminoglycosides in the absence and presence of an efflux pump inhibitor. All the isolates were also tested by polymerase chain reaction for the presence of mexA, mexC, and mexE efflux genes. Results: Of the isolates, 81 (89%) and 83 (91.2%) were multidrug resistant according to the disk diffusion and MIC method, respectively. Cross-resistance was observed in 67 (73.6%) and 68 (74.7%) of isolates according to the disk diffusion and MIC method, respectively. In the presence of the efflux pump inhibitor, twofold or higher MIC reduction to imipenem, cefepime, ciprofloxacin, and gentamicin was observed in 59, 65, 55, and 60 isolates, respectively. Except for two isolates that were negative for mexC, all isolates were positive for mexA, mexC, and mexE genes simultaneously. Conclusion: Efflux pumps could cause different levels of resistance based on their expression in clinical isolates. Early detection of different efflux pumps in P. aeruginosa could allow the use of other antibiotics and efflux pump inhibitors in combination with antibiotic therapy.

scholarly journals EFFLUX PUMP OVEREXPRESSION PROFILING IN ACINETOBACTER BAUMANNII AND STUDY OF NEW 1-(1-NAPHTHYLMETHYL)-PIPERAZINE ANALOGS AS POTENTIAL EFFLUX INHIBITORS

2021 ◽  
Author(s):  
Morgane Choquet ◽  
Elodie Lohou ◽  
Etienne Pair ◽  
Pascal Sonnet ◽  
Catherine Mullie
Keyword(s):  
Antibiotic Resistance ◽  
Acinetobacter Baumannii ◽  
Inhibitory Activity ◽  
Efflux Pump ◽  
Parent Compound ◽  
Efflux Pumps ◽  
Quinoline Derivative ◽  
Genes Encoding ◽  
Efflux Pump Inhibitors ◽  
Therapeutic Alternatives

Overexpression of efflux pumps extruding antibiotics currently used for the treatment of Acinetobacter baumannii infections has been described as an important mechanism causing antibiotic resistance. The first aim of this work was to phenotypically evaluate the overexpression of efflux pumps on a collection of 124 ciprofloxacin resistant A. baumannii strains. An overexpression of genes encoding one or more efflux pumps was obtained for 19 out of the 34 strains with a positive phenotypic efflux (56%). The most frequent genes overexpressed were those belonging to the RND family, with adeJ being the most prevalent (50%). Interestingly, efflux pump genes coding for MATE and MFS families were also overexpressed quite frequently: abeM (32%) and abaQ (26%). The second aim was to synthesize 1-(1-NaphthylMethyl)-Piperazine analogs as potential new efflux pump inhibitors and biologically evaluate them against strains with a positive phenotypic efflux. Quinoline and pyridine analogs were found to be more effective than their parent compound 1-(1-NaphthylMethyl)-Piperazine. Stereochemistry also played an important part in the inhibitory activity as quinoline derivative ( R )-3a was identified as being the most effective and less cytotoxic. Its inhibitory activity was also correlated to the number of efflux pumps expressed by a strain. The results obtained in this work suggest that quinoline analogs of 1-(1-NaphthylMethyl)-Piperazine are promising leads in the development of new anti- Acinetobacter baumannii therapeutic alternatives, in combination with antibiotics for which an efflux-mediated resistance is suspected.

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.

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