Novel phytochemical–antibiotic conjugates as multitarget inhibitors of Pseudomononas aeruginosa GyrB/ParE and DHFR

Abstract

BackgroundThere is a dearth of treatment options for community-acquired and nosocomial Pseudomonas infections due to several rapidly emerging multidrug resistant phenotypes, which show resistance even to combination therapy. As an alternative, developing selective promiscuous hybrid compounds for simultaneous modulation of multiple targets is highly appreciated because it is difficult for the pathogen to develop resistance when an inhibitor has activity against multiple targets.MethodsIn line with our previous work on phytochemical–antibiotic combination assays and knowledge-based methods, using a fragment combination approach we here report a novel drug design strategy of conjugating synergistic phytochemical–antibiotic combinations into a single hybrid entity for multi-inhibition of P. aeruginosa DNA gyrase subunit B (GyrB)/topoisomerase IV subunit B (ParE) and dihydrofolate reductase (DHFR) enzymes. The designed conjugates were evaluated for their multitarget specificity using various computational methods including docking and dynamic simulations, drug-likeness using molecular properties calculations, and pharmacophoric features by stereoelectronic property predictions.ResultsEvaluation of the designed hybrid compounds based on their physicochemical properties has indicated that they are promising drug candidates with drug-like pharmacotherapeutic profiles. In addition, the stereoelectronic properties such as HOMO (highest occupied molecular orbital), LUMO (lowest unoccupied molecular orbital), and MEP (molecular electrostatic potential) maps calculated by quantum chemical methods gave a good correlation with the common pharmacophoric features required for multitarget inhibition. Furthermore, docking and dynamics simulations revealed that the designed compounds have favorable binding affinity and stability in both the ATP-binding sites of GyrB/ParE and the folate-binding site of DHFR, by forming strong hydrogen bonds and hydrophobic interactions with key active site residues.ConclusionThis new design concept of hybrid “phyto-drug” scaffolds, and their simultaneous perturbation of well-established antibacterial targets from two unrelated pathways, appears to be very promising and could serve as a prospective lead in multitarget drug discovery.

A Novel Antimicrobial–Phytochemical Conjugate With Antimicrobial Activity Against Streptococcus uberis, Enterococcus faecium, and Enterococcus faecalis

“…However, the biodistribution and metabolism profiles of the phytochemicals may not coincide with those of the antimicrobials, and thus challenging the antimicrobial–phytochemical combination therapies on whether the optimal therapeutic efficacy is really achieved. To overcome this obstacle, we adopted an in silico approach to design novel antimicrobial–phytochemical conjugate compounds (i.e., conjugate the active parts of antimicrobials and phytochemicals based on computer-aided molecular simulations) (Jayaraman et al, 2013). In the current study, we report the synthesis of a sulfamethoxazole–gallic acid conjugate (hybrid 1) and the evaluation of its antimicrobial activity against three bacterial stains purchased from the American Type Culture Collection (ATCC) and two E. faecalis clinical isolates (designated as isolates 1 and 2) from a Saskatchewan poultry farm.…”

Multi-target pharmacology: possibilities and limitations of the “skeleton key approach” from a medicinal chemist perspective

“…Including some degree of flexibility in the molecule may help the common and non-common pharmacophoric features to accommodate to the correspondent binding sites of the different intended targets; however, the degree of flexibility should be carefully tuned so that an excess of flexibility does not conspire against the binding affinity (owing to unfavorable entropic loss associated to the binding event) or the bioavailability of the drug (it should be remembered that many druglikeness rules limit the number of flexible bonds in the molecule). An illustrative example of some of these principles is provided by the recent research from Jayaraman et al (2013) . These authors applied the fragment-based approach in the design of phytochemical-antibiotic conjugates conceived as multivalent inhibitors of Pseudomonas aeruginosa DNA gyrase subunit B (GyrB)/topoisomerase IV subunit B, dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS).…”

Challenges and future prospects of antibiotic therapy: from peptides to phages utilization

“…Recently interaction studies are drawn to study the associated effects of antibiotic and phytochemicals (Sakharkar et al, 2009; Jayaraman et al, 2013). A current study revealed that phytochemical-antibiotic conjugates have multitarget inhibitors of Pseudomononas aeruginosa GyrB/ParE and DHFR was extremely effective (Jayaraman et al, 2010).…”