Abstract
Antibiotic resistance is on the rise and has become one of the biggest public health challenges of our time. Bacteria are able to adapt to the selective pressure exerted by antibiotics in numerous ways, including the (over)expression of efflux pumps, which represents an ancient bacterial defense mechanism. Several studies show that overexpression of efflux pumps rarely provides clinical resistance but contributes to a low-level resistance, which allows the bacteria to persist at the infection site. Furthermore, recent studies show that efflux pumps, apart from pumping out toxic substances, are also linked to persister formation and increased spontaneous mutation rates, both of which could aid persistence at the infection site. Surviving at the infection site provides the low-level-resistant population an opportunity to evolve by acquiring secondary mutations in antibiotic target genes, resulting in clinical resistance to the treating antibiotic. Thus, this emphasizes the importance and challenge for clinicians to be able to monitor overexpression of efflux pumps before low-level resistance develops to clinical resistance. One possible treatment option could be an efflux pump-targeted approach using efflux pump inhibitors.
Highlights
Antibiotic resistance is one of the biggest public health challenges of our time
In spite of the fact that increased expression of efflux pumps does not provide clinical resistance per se, efflux pump-mediated low-level-resistant bacteria might persist at the infection site, which could present an opportunity to evolve into high-level clinical resistance through the acquisition of additional mutations
M. tuberculosis cells with low-level resistance to isoniazid caused could be resolved, which makes it feasible to implement a combinatorial antibacterial therapy, which in theory could include the use of efflux pump inhibitors, targeting and eradicating all phenotypes in the infecting bacterial population [25]
Summary
Antibiotic resistance is one of the biggest public health challenges of our time. During the “golden era” of antibiotic discovery (e.g., 1940s through 1960s), effective novel antibiotics were frequently discovered and introduced to the market. The current global antibiotic resistance crisis is a result of massive antibiotic consumption both in the clinic and in agriculture along with a progressively declining introduction of novel antibiotics [1,2]. Even if an antibiotic is successfully introduced to the market, its use in the clinic will drop as resistance to it inevitably develops. The bacterial cell envelope has the ability to prevent the entry of antibiotics into the cell (“permeability barrier”); it is increasingly recognized that the function of efflux pumps, acting either alone or along with decreased expression of porins, constitutes parts of this “barrier” [4]. Genes encoding efflux pumps are found on both plasmids (e.g., transmissible elements) or on the chromosome. We will focus on the chromosomally encoded efflux pumps
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