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

BACKGROUND: There 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. METHODS: In 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. RESULTS: Evaluation 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. CONCLUSION: This 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.

Comparison of human and porcine aortic valves.

We compared the anatomy of human and porcine aortic valves. Porcine hearts were collected from the abattoir. Human hearts from patients who had died of non-cardiac causes were examined in the mortuary; only undamaged and anatomically normal hearts were used. Silicon casts were prepared by injecting engineering silicon at 80 mm Hg into the aortic arch. Various features of the aortic valve were measured: circumference, length between the commissural end point and central point of coaptation, surface diameter, and surface area. In total, 12 porcine and 12 human aortic valves were studied. The average circumferences of the human and porcine aortic valves were 8.00 +/- 0.2 (SD) cm and 7.90 +/- 1.0 cm, respectively. The central point of coaptation in human valves was skewed toward the left coronary cusp, whereas in porcine valves it was skewed toward the non-coronary cusp. In human aortic valves, the non-coronary cusp had the largest surface diameter and surface area with mean measurements of 3.6 +/- 0.2 cm and 1.230 +/- 0.228 cm(2), respectively; the left coronary cusp was smallest for the same variables with measurements of 3.1 +/- 0.3 cm and 0.898 +/- 0.357 cm(2). In porcine valves, the right coronary cusp had the largest surface diameter and surface area with mean measurements of 3.9 +/- 0.7 cm and 1.716 +/- 0.81 cm(2), respectively; the non-coronary cusp was the smallest for the same variables with measurements of 2.9 +/- 0.5 cm and 1.023 +/- 0.659 cm(2). These differences suggest that when using porcine valves as transplant material (e.g., stentless valves), geometric considerations, such as commissural length, may be important.