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Middleton started his career by becoming a Justice of Peace, and soon after, a member of the King's Council in America.
He became a member of the South Carolina House of Commons where he was elected speaker a total of 3 times.
He became Commissioner of Native American Affairs in 1755, and was elected to the South Carolina Colonial Council.
Middleton gained recognition for his courageous, calm and steady temperament during the Anglo-Cherokee War between 1760 and 1761.
He resigned from public offices in 1770, to focus on business.

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