Their novel method for growing bacteria has yielded 25 new antibiotics, with one deemed "very promising".
The last new class of antibiotics to make it to clinic was discovered nearly three decades ago.
The study, in the journal Nature, has been described as a "game-changer" and experts believe the antibiotic haul is just the "tip of the iceberg".
The heyday of antibiotic discovery was in the 1950s and 1960s, but nothing found since 1987 has made it into doctor's hands.
Since then microbes have become incredibly resistant. Extensively drug-resistant tuberculosis ignores nearly everything medicine can throw at it.
Back to soil
The researchers, at the Northeastern University in Boston, Massachusetts, turned to the source of nearly all antibiotics - soil.
This is teeming with microbes, but only 1% can be grown in the laboratory.
The team created a "subterranean hotel" for bacteria. One bacterium was placed in each "room" and the whole device was buried in soil.
It allowed the unique chemistry of soil to permeate the room, but kept the bacteria in place for study.
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