TB is caused by infection with mycobacterium tuberculosis
Two drugs already used for fighting other infections may help in the battle against drug-resistant tuberculosis, researchers say.
The combination of clavulanate and meropenem was effective against 13 strains of the most drug resistant TB in the laboratory.
Clinical trials are now being planned by the US researchers, who reported their results in the Science journal.
UK experts urged caution but said new TB treatments were desperately needed.
It is thought one-third of the world's population is infected with TB - 10% of whom develop active disease.
There is growing concern about extensively drug resistant disease - known as XDR-TB - against which first choice and at least one second choice treatments do not work.
The latest study revisits the effectiveness of beta-lactam antibiotics, the family which includes penicillin and is very widely used in the treatment of infection but has never been successful against TB.
This lack of effectiveness is largely because the mycobacterium tuberculosis bacterium contains a highly active enzyme which inactivates the antibiotics.
In the latest study, researchers looked at several combinations of one drug to stop the enzyme working and one beta-lactam antibiotic.
They found that clavulanate was the best enzyme inhibitor and meropenem, a fairly modern antibiotic, the best partner in potently killing different strains of TB.
Clinical trials are being planned later this year.
Professor John Blanchard, a biochemist from Albert Einstein College of Medicine in New York, said the idea of using these drugs in tandem was not new but what they had done was carry out a detailed investigation into what combination may work against TB.
He explained that the drugs also seemed to work against TB in the non-active phase which is notoriously difficult to treat.
"The number of untreatable cases is increasing worldwide every year.
"We are excited about this because, with the caveat that this needs to be shown to be effective in controlled clinical trials, this would be the first new drug to be introduced in the treatment of TB in 40 years."
Professor Denis Mitchison, an expert in medical microbiology at St George's, University of London, said the theory of using a penicillin and clavulanate was not a new one but such combinations had not been sufficiently effective in the past.
"The use of merepenems is new and the combination now sounds effective, though there are already reports of rare resistant strains of other bacteria."
He urged caution about using the drug combination alone.
But he added: "The more drugs that can be used in the treatment of multidrug resistant and XDR-TB, the better."
Dr Ruth McNerney, a TB expert at the London School of Hygiene and Tropical Medicine, said the drug combination needed to be tested in patients before any conclusions could be drawn.
"But we desperately need drugs for XDR-TB," she added.