Targeted activation instead of continuous operation: how bacteria save energy and what this has to do with antibiotic resistance

Antibiotic resistance is one of the greatest global health risks. A research team at Friedrich Schiller University in Jena has now uncovered a previously unknown mechanism by which bacterial transport proteins precisely link energy consumption to the release of antibiotics. The findings provide new approaches for specifically weakening resistance. The study has been published in the journal Nature Communications.

How bacteria transport antibiotics out of the cell

Many bacteria evade the effects of antibiotics by actively pumping them out of the cell. They do this with the help of so-called multi-drug pumps, which can recognise and remove a wide variety of substances. A particularly important group are the so-called ABC transporters, which use the energy carrier molecule ATP for this process.

‘These transporters are highly efficient molecular machines,’ says Prof. Dr. Ute Hellmich, Professor of Biomolecular NMR Spectroscopy at the University of Jena, who led the research project in the ‘Balance of the Microverse’ Cluster of Excellence. ‘They ensure that antibiotics don't even get to where they are supposed to cause damage.’

Until now, however, it was unclear how certain processes in these transporters are coordinated: the binding of the antibiotic on the one hand and the binding and consumption of ATP on the other – because these two processes take place far apart from each other, much like a furnace in the basement can heat a room on the third floor. ‘Consuming energy without transporting an antibiotic would be extremely inefficient for the cell,’ explains Hellmich. ‘Conversely, there is no point in binding an antibiotic if transport is not triggered.’

A molecular ‘communication hinge’

In their current study, the researchers were able to show for the first time that both processes are bidirectionally linked. The key to this is a small set of specific amino acids in the transport protein, which acts like a molecular communication hinge. This hinge registers whether both ATP and an antibiotic are bound and then coordinates energy consumption and transport in a targeted manner.

‘You can think of it as a security check,’ says Hellmich. ‘Only when both signals are present at the same time does the pump switch to active mode. In this way, the cell prevents valuable energy from being wasted.’

Approaches to combating antibiotic resistance

When the researchers specifically alter this hinge through mutations, the two processes become decoupled: ATP continues to be consumed, but the active substance is no longer transported. The results thus provide new mechanistic insight into the functioning of resistance pumps – and open up potential approaches for new antibiotics. ‘If we succeed in specifically disrupting this internal communication in the antibiotic pump, existing antibiotics could become more effective again,’ says Hellmich. ‘This is an exciting approach in the fight against multi-resistant germs.’

Original publication:

Victor Hugo Pérez Carrillo, Margot Di Cesare, Dania Rose-Sperling, Waqas Javed, Hannes Neuweiler, Julien Marcoux, Cédric Orelle, Jean-Michel Jault, Ute A. Hellmich, ‘Bidirectional communication between nucleotide and substrate binding sites in a type IV multidrug ABC transporter’, Nature Communications, 2025, DOI: 10.1038/s41467-025-65037-y