Abstract
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.
Highlights
Antimicrobial resistance (AMR) is a natural phenomenon and an intrinsic property of bacteria that occurs upon exposure to antibiotics due to their genetic flexibility and adaptability
In addition to the ESKAPEE pathogens (Enterococcus faecium., Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp. and Escherichia coli), biofilm production has been reported to be prevalent in Gram-positive (Bacillus spp., Listeria monocytogenes and lactic acid bacteria [17]) and other Gram-negative bacteria (Klebsiella oxytoca, Proteus vulgaris, Proteus mirabilis, and Morganella morganii [18])
This was suggestive of the role of the efflux-based system in ciprofloxacin resistance in the pathogen and further highlights the ability of carbonyl cyanide 3-chlorophenylhydrazone (CCCP) to inhibit the previously mentioned efflux pumps
Summary
Antimicrobial resistance (AMR) is a natural phenomenon and an intrinsic property of bacteria that occurs upon exposure to antibiotics due to their genetic flexibility and adaptability. Over the years, this process has been grossly accelerated through the overuse, inappropriate prescribing and extensive agricultural use of antibiotics and other antimicrobial agents This process, termed acquired resistance, has resulted in the emergence of multi-drug resistant (MDR) bacteria. Acquired resistance can caused by horizontal gene transfer (HGT), orof spontaneous chromosomal force of multi-drug resistanceof rise, is the transfer of resistance between bacteriadriving throughforce the use mutations, or a combination both factors [3,4]. The underlying biochemical basis for multi-drug resistance rise, is the transfer of resistance gene between bacteria through the use of AMR include several mechanisms such asand drug inactivation/alteration through hydrolysisbasis or other exogenous genes: Plasmids, transposons integrons [4].
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