One "man of destiny" was James Wilkinson. Perhaps because of Wilkinson's machinations during the Revolutionary War where he played a role in undercutting General George Washington's authority in the Conway Cabal, President Washington was not a fan of Wilkinson's. "Washington, who had wanted Wilkinson watched, had retired to Mount Vernon. John Adams gave the general his confidence and maintained him in the southwest." [Devil's Backbone]
James Wilkinson was a former partner of Daniel Clark, who later wrote a public condemnation against Wilkinson. Wilkinson's own memoirs characterized Daniel Clark as a man "untrue to the country of his birth, untrue to his friends, untrue in his sworn depositions...".
"A young lawyer, Nicholas Perkins, took his suspicions (that Burr was in the area) to Capt. Edmund P. Gaines, who had helped survey the Natchez Trace. Gaines, then on duty at nearby Fort Stoddert, arrested the disguised Burr (February 1807). Burr was found "not guilty" of treason at his trial in Richmond, Virginia." (From the Devil's Backbone)
As General Jackson, he moved troops down the Natchez Trace from Tennessee to the Battle of New Orleans; as Andrew Jackson, he and Rachel were married at the Springfield Plantation in Natchez, Mississippi. Andrew Jackson knew James Wilkinson and detested him.
Meriwether Lewis and the Harpe brothers are an inextricable part of the Trace history:
On October 11, 1809, Meriwether Lewis died "under mysterious circumstances" on the Natchez Trace. The Harpe brothers, Micajah, "Big Harpe," and Wylie, "Little Harpe," were feared and notorious killers who prowled the Natchez Trace.
From the "Devil's Backbone:" Only a poet long afterwards, recalling sin, retribution, and a poisoned lineage, connected the event with the murder of their slave, committed by Thomas Jefferson's nephews (Lewis boys) on the night the earthquakes began. No historian can count any special significance in the fact that less than ten days after the quakes began, General Wilkinson was found 'not guilty' by a court-martial verdict so worded that President Madison approved it 'with regret.' This was the trial prompted by the publication of Daniel Clark's Proofs of the Corruption of Gen. James Wilkinson.