Artemisinin, derived from a Chinese herb, has become the drug of choice for treating malaria after chloroquine, introduced in the 1950s, was rendered useless by resistance.
Researchers from the French-led Pasteur Institute Network took blood samples in 2001 from 530 malaria patients in Cambodia, French Guiana and Senegal, where there are different patterns of artemisinin use.
They then tested the samples in lab dishes, exposing the parasite, Plasmodium falciparum, to a range of malaria drugs.
Some samples from French Guiana and Senegal, where use of artemisinin is uncontrolled, showed signs of being insensitive to that drug. But samples from Cambodia, where the drug is controlled, showed no sign of resistance.
"All resistant isolates [samples] came from areas with uncontrolled use of artemisinin derivatives," said lead scientist Ronan Jambou in Saturday's edition of the British medical weekly.
"This rise in resistance indicates the need for increased vigilance and a coordinated rapid deployment of drug combinations."
Its publication comes on the heels of a call on 6 September by the World Health Organisation (WHO), which called on countries to be extremely vigilant in the use of artemisinin-based drugs to avoid stoking resistance.
The new research pinpoints the problem to mutations in a gene in the parasite called SERCA-type Prtpase6 that is targeted by artemisinin.
Resistance by a bacteria, virus or parasite is encouraged when a patient fails to take a full course of drugs or uses drugs that are counterfeit or diluted.
Malaria kills around a million people every year and at least 300 million cases of acute malaria occur each year, according to the WHO, although some experts suggest this is a serious under-estimate.