Preheat oven to 350°F. Grease a 9x13 baking dish with butter. Bring large pot of salted water to boil.
Cook 1 pound small macaroni for 6-7 minutes until just under al dente. Drain and set aside.
Melt 4 tablespoons butter in Dutch oven over medium heat. Whisk in 1/3 cup flour and cook 3-4 minutes until golden and nutty.
Gradually whisk in 4 cups warm milk and 1 cup heavy cream. Cook 5-7 minutes until thickened enough to coat spoon.
Reduce heat to low. Stir in garlic powder, onion powder, smoked paprika, and mustard powder. Remove from heat.
Fold in 4 cups cheddar and 2 cups mozzarella, one cup at a time, until smooth. Season with salt and pepper.
Add cooked macaroni to cheese sauce and stir until thoroughly coated. Transfer to prepared baking dish.
Optional: Melt remaining 2 tablespoons butter and toss with panko breadcrumbs. Scatter over top.
Bake uncovered 25-30 minutes until bubbly and golden. Rest 10 minutes before serving.