After six weeks of labor to build a fort and church, the expedition was attacked by Calusa aborigines. Ponce was wounded in the thigh by an arrow, and gangrene set in. The entire colony returned in haste to Havana, where Ponce died of his wound.

The American mainland was opened for European settlement by the Hernando DeSoto expedition of 1539-42. Chronicles of survivors and research of 16th-century ship drafts by Sun-Herald historian-columnist Lindsey Williams indicate the explorer landed at Live Oak Point on the north shore of Charlotte Harbor. The official Florida DeSoto Trail Commission has acknowledged that the Charlotte Harbor landing is as feasible as any other -- pending archaeological proof.

The Spanish explorer Pedro Menedez D'Aviles, who established the first American colony at St. Augustine, Florida, in 1565, built a mission-fort named San Antonio somewhere in the Charlotte Harbor complex the following year. After two years of alternate cooperation and bloody warfare between the Spaniards and the Calusa, Menendez abandoned his efforts to pacify the fierce Indians of southern Florida.