The Impact of Efflux Pump Inhibitors on the Activity of Selected Non-Antibiotic Medicinal Products against Gram-Negative Bacteria.

Agnieszka Laudy,Ewa Kulińska,Stefan Tyski

doi:10.3390/molecules22010114

Agnieszka Laudy, Ewa Kulińska + Show 1 more

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https://doi.org/10.3390/molecules22010114

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Abstract

The potential role of non-antibiotic medicinal products in the treatment of multidrug-resistant Gram-negative bacteria has recently been investigated. It is highly likely that the presence of efflux pumps may be one of the reasons for the weak activity of non-antibiotics, as in the case of some non-steroidal anti-inflammatory drugs (NSAIDs), against Gram-negative rods. The activity of eight drugs of potential non-antibiotic activity, active substance standards, and relevant medicinal products were analysed with and without of efflux pump inhibitors against 180 strains of five Gram-negative rod species by minimum inhibitory concentration (MIC) value determination in the presence of 1 mM MgSO4. Furthermore, the influence of non-antibiotics on the susceptibility of clinical strains to quinolones with or without PAβN (Phe-Arg-β-naphthylamide) was investigated. The impacts of PAβN on the susceptibility of bacteria to non-antibiotics suggests that amitriptyline, alendronate, nicergoline, and ticlopidine are substrates of efflux pumps in Gram-negative rods. Amitriptyline/Amitriptylinum showed the highest direct antibacterial activity, with MICs ranging 100–800 mg/L against all studied species. Significant decreases in the MIC values of other active substances (acyclovir, atorvastatin, and famotidine) tested with pump inhibitors were not observed. The investigated non-antibiotic medicinal products did not alter the MICs of quinolones in the absence and in the presence of PAβN to the studied clinical strains of five groups of species.

Highlights

One of the most serious healthcare problems today is the increasing prevalence of antibiotic-resistant Gram-negative bacterial strains
There is an urgent need for both the discovery of new chemical compounds with potent and broad antibacterial activity and a search for methods enabling the restoration of bacterial susceptibility to known antibacterial agents
Relying on our previous article concerning the influence of efflux pump inhibitors on the activity of non-antibiotic non-steroidal anti-inflammatory drugs (NSAIDs) against Gram-negative rods [6], we have decided to investigate whether non-antibiotic drugs from the other therapeutic groups are substrates for MDR efflux pumps of Gram-negative rods

Summary

Introduction

One of the most serious healthcare problems today is the increasing prevalence of antibiotic-resistant Gram-negative bacterial strains. The coexistence and cooperation of different drug-resistance mechanisms (e.g., the production of enzymes that destroy antibiotics and overexpression of the multidrug (MDR) efflux pumps that remove drugs from the cells of clinical bacterial isolates) make infectious diseases treatment difficult and ineffective [1,2,3]. Very important and dangerous for infected people is the phenomenon of removal of antibiotics belonging to different chemical groups from the bacteria by RND efflux systems [2,3]. Looking for effective antibacterial agents among known medicinal products from the group of “non-antibiotics”, drugs belonging to different therapeutic groups that are used in the management of pathological symptoms of a non-infectious aetiology, is a interesting strategy [4,5]. The potential role of non-antibiotics in the treatment of multidrug-resistant Gram-negative bacteria has recently been investigated

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