Its swirling winds and rain will be a major test of the region's new flood control systems seven years after Hurricane Katrina sent walls of water crashing inland.

The U.S. National Hurricane Center said at 5 a.m. ET on Tuesday that Isaac was still a tropical storm but was likely to become a hurricane during the day as it gains strength over the Gulf of Mexico.

The center of the storm was located about 125 miles south-southeast of the mouth of the Mississippi River and had top sustained winds of 70 mph, the Hurricane Center said. 

Follow Isaac's path with our storm tracker

It was moving to the northwest at 12 mph and appeared to be taking direct aim at New Orleans, which would be a cruel blow for a city still struggling to recover from Katrina which swept across the city on Aug. 29, 2005, killing more than 1,800 people and causing billions of dollars of damage. 

NOAA via EPA

A satellite image shows Tropical Storm Isaac in the Gulf of Mexico on Tuesday.

Unprotected, low-lying areas outside New Orleans were evacuated Monday.

From weather.com: Live updates and analysis

"All preparations to protect life and property should be completed tonight," said Ed Rappaport of the National Hurricane Center in his 8 p.m. ET Monday update. He emphasized that water from rain and storm surge would be the biggest threat -- 6 to 18 inches of rain were expected.

Isaac has killed at least 22 people and caused significant flooding and damage in Haiti and the Dominican Republic before skirting the southern tip of Florida on Sunday.

Storm surge fears
The storm was forecast to strengthen into a Category 1 hurricane, the lowest on the five-step Saffir-Simpson scale of hurricane intensity, with top winds of 90 miles per hour.

While that would be well below the intensity of Katrina, a powerful Category 3 storm, the vast size of Isaac's slow-moving system has forecasters predicting widespread flooding. 

"Even if it is a tropical storm at landfall, the large size of it will still generate significant storm surge," Hurricane Center Director Rick Knabb told reporters on Monday. "That is life-threatening potentially." 

Residents in coastal communities from Louisiana to Mississippi stocked up on food and water and tried to secure their homes, cars and boats. 

Chris Graythen / Getty Images

New Orleans' Bourbon street remains virtually empty on Monday ahead of Isaac's landfall.

In New Orleans, a bumper-to-bumper stream of vehicles left the city on a highway toward Baton Rouge in search of higher ground. Others prepared, or were forced, to ride the storm out.

South hopes for drought relief from Isaac

"Our flights were canceled so we're going to be here," said Karen Foley, a 23-year-old tourist who had planned to travel home to New Jersey with a friend. "We are just hoping the city doesn't get hit again. It doesn't deserve it," she said.