Antibiotic resistant bacteria are frightening. When resistant, the bacteria are not affected by the drugs usually employed to kill them (antibiotics). Some postulate that such “superbugs” might even spell the end for humanity in the too-near future. To study bacterial resistance, Nathalie Q. Balaban from the Hebrew University of Jerusalem and fellow infectious disease experts tracked the evolution of methicillin-resistant Staphylococcus aureus (MRSA, pronounced mur-suh) extracted from the blood of infected patients at the Shaare Zedek Medical Center. In their January 2020 Science article, they explore MRSA resistance under combinations of the antibiotic treatments rifampicin (RIF) and daptomycin (DAP).

“The Illusion of Drugs” by Eyad Elbayoumi is licensed under CC BY 2.0

In one patient, MRSA developed resistance to RIF after receiving the combination of DAP and RIF antibiotics. This was not good news since combination treatment should, in theory, help prevent resistance. However, the finding helped the researchers discover more information about the evolution of bacteria.

Before resistance develops, bacteria could acquire tolerance mutations. When tolerant, bacteria become temporarily dormant (i.e. stop growing) to evade the effects of antibiotic treatment, which only functions on actively growing bacteria. Tolerance lasts a few days and is called the tolerance window. Since RIF reduces DAP’s killing power and is therefore considered suppressive, an initial DAP treatment was shown to work more effectively than the combination of RIF and DAP. The results suggest that doctors should first prescribe DAP only, ideally before the tolerance window.

“We observed that bacteria acquired tolerance within a few days. These tolerance mutations then acted as a stepping stone to acquire resistance and, ultimately, treatment failure,” described Balaban.

Balaban highlighted the importance of treating patients not just before resistance develops, but also before tolerance develops. The results indicate a counterintuitive approach: monotherapy might could be more effective than combination therapy. Balaban’s conclusions suggest that antibiotics don’t necessarily need to become stronger, but instead just prescribed more effectively. Further, the findings could improve both the prescription patterns of doctors and patient prognoses.

“Using the right combination of available antibiotic drugs at the outset could dramatically increase a patients’ survival rate before their infection becomes tolerant to all the antibiotics in our arsenal,” Balaban concluded.

Thanks to the work of Balaban and colleagues, the superbug apocalypse might just have gotten a rain check.


Liu J, Gefen O, Ronin I, Bar-Meir M, Balaban NQ. 2020. Effect of tolerance on the evolution of antibiotic resistance under drug combinations. Science 367: 200–204.