"As a bowler you block out who you're bowling to but he's obviously an fantastic player", Mitchell Marsh said of De Villiers, having trapped Du Plessis and De Bruyn lbw.
Amla was twice given out lbw, but got the decisions overturned on 7 and 40 on DRS.
Australia otherwise battled to create opportunities to take wickets, not helped by South Africa going into their shell and playing risk-free cricket, though spinner Nathan Lyon did find good turn off the wicket and was hard to score off.
While de Kock perished in the final hour of the day, Vernon Philander kept de Villiers company to the close, seeing off the first five overs of the second new ball.
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The EU, Brazil and Britain were also quick to launch broadsides against the tariffs , which are worth billions of dollars. The US leader had also added Australia to a list of likely carve-outs, as a "great country" and "long term partner".
Cummins, Hazlewood and Mitchell Starc put the clamps on South Africa's scoring but couldn't take the big breakthrough.
One of the elements that livened up a slow day out in the middle, the brass band that has been a popular fixture at St George's Park for two decades, was asked to stop playing by umpires Kumar Dharmasena and Sundaram Ravi. The resulting boundary brought up his half-century in 164 balls.
SUMMARY: South Africa hold a 20-run lead. But after tea, they tumbled to 183 for six and were in danger of a deficit.
Mitchell Starc removes Hashim Amla's off stump with a pinpoint yorker shortly after tea.
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That was the fourth ball of the third session, and Hazelwood returned immediately from the other end.
De Villiers was a class above his team-mates and the tourists' disciplined bowling, counter-attacking when the game was in the balance to drag his side towards first-innings ascendancy.
Medium-pacer Marsh trapped South African captain Faf du Plessis and Theunis de Bruyn leg before wicket, again with full, swinging deliveries. Unbeaten on 74 from 81 balls, De Villiers has been the only player in the match who has made batting look comfortable on a slow pitch on which both sides have been able to produce prodigious reverse-swing.
When de Kock was undone by a classic offspinner's dismissal to a left-hander - the delivery from Lyon from around the wicket dipped and turned past the outside edge to hit the top of off-stump - de Villiers reined himself in a touch.
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Ronaldo opened the scoring against the flow of play in the 34th minute when Luka Modric intercepted a pass and set him up. But Ronaldo proved the difference again, the 33-year-old taking his tally for the season to 35 goals in 37 appearances.
Pat Cummins went close to dismissing De Villiers with a brute of a bouncer in the 75th over, at which point the gifted batsman was on 15 and the Proteas were 175 for four.