Phytochemicals increase the antibacterial activity of antibiotics by acting on a drug efflux pump

Abstract

Drug efflux pumps confer resistance upon bacteria to a wide range of antibiotics from various classes. The expression of efflux pumps are also implicated in virulence and biofilm formation. Moreover, organisms can only acquire resistance in the presence of active drug efflux pumps. Therefore, efflux pump inhibitors (EPIs) are attractive compounds to reverse multidrug resistance and to prevent the development of resistance in clinically relevant bacterial pathogens. We investigated the potential of pure compounds isolated from plants to act as EPIs. In silico screening was used to predict the bioactivity of plant compounds and to compare that with the known EPI, phe-arg-β-naphthylamide (PAβN). Subsequently, promising products have been tested for their ability to inhibit efflux. Plumbagin nordihydroguaretic acid (NDGA) and to a lesser degree shikonin, acted as sensitizers of drug-resistant bacteria to currently used antibiotics and were able to inhibit the efflux pump-mediated removal of substrate from cells. We demonstrated the feasibility of in silico screening to identify compounds that potentiate the action of antibiotics against drug-resistant strains and which might be potentially useful lead compounds for an EPI discovery program.

Efflux pump inhibitors of clinically relevant multidrug resistant bacteria

“…It decreased the MIC values of erythromycin, chloramphenicol, and tetracycline with an MPC 4 of 847 µM against E. coli BW25113 (a wild type, drug‐resistant strain). Although this compound is still of low potency it is a good example of how useful the in silico approach can be in identifying novel, structurally diverse inhibitors that could serve as lead compounds in the design of more potent EPIs . However, NDGA also possesses activity against several other enzymes with different biological functions at even lower doses than those required for EPI, which hinders its further development as a selective EPI …”

“…In keeping with the systematic development of EPIs in Gram-negative bacteria, some polyphenolic compounds, that were identified as inhibitors of AcrB on in silico screening, should also be noted. 238 A database of 50 phytochemicals was evaluated and binding to AcrB was studied with docking experiments. The docking of the known inhibitor PAβN (1; Figure 1) was used for comparison.…”

Multidrug efflux pumps and their role in antibiotic and antiseptic resistance: a pharmacodynamic perspective

“…But the development of inhibitors targeting RND component of efflux pump is now the main approach that is described and tested in gram-negative bacteria. Several series of compounds from both natural [68,69] and synthetic [70][71][72][73][74] sources displaying an EPI activity have been identified (Table 1). Structure-activity relationship (SAR) studies give relevant information about the molecular and the physicochemical properties of EPIs useful in pharmacophore models to describe features that bind the target [75,76].…”

Equibiotics: a new type of phyto-drug equilibrating local microbiota

“…In addition, everything seems to indicate that the flavonoid and alkaloidal effects are also related to their ability to interfere with efflux pumps and the mechanism of "quorum sensing" (QS) of undesirable bacteria in the ecosystem, a complex mechanism of action yet to be tested experimentally [34][35][36][37][38].…”