Breakthrough Discovery: How Membrane Proteins Aid Bacteria’s Resistance to Antibiotics

In a groundbreaking study, researchers from Cornell University and the University of California, San Francisco (UCSF), have identified a key mechanism that allows bacteria to resist antibiotics. This finding provides valuable insights into a critical area of medical research and could potentially lead to new strategies for combating bacterial resistance.

The MacAB-TolC Protein Complex

The scientists focused on a protein complex known as MacAB-TolC, which acts as a multidrug efflux pump in gram-negative bacteria. This complex spans the cell’s inner and outer membranes, as well as the periplasm, a space between the inner and outer membranes. The MacAB-TolC pump enables bacteria to expel antibiotics as well as other substances that might harm them.

In detail, the complex is composed of MacA, MacB, and TolC proteins. TolC resides in the outer membrane, MacB in the inner membrane, and MacA in the periplasm. These proteins must come together in specific proportions—two MacBs, six MacAs, and three TolCs—to form the pump. Until now, it was unclear how substrates enter the pump and what happens once the structure is assembled.

The Surprising Discovery

Using single-molecule imaging, the study authors examined protein concentrations within Escherichia coli (E. coli) cells. To their surprise, they found that the MacAB-TolC complex existed with an excess of MacB and TolC proteins. This imbalance, far beyond the necessary 2:6:3 stoichiometry, prompted further investigation into the protein dynamics and their functional implications.

Peng Chen, Ph.D., lead author of the study and a professor of chemistry at Cornell University, explained, “You basically have these extra Bs that don’t have A partners to assemble. And of course, the cell does not do this for no reason.” His team found that these unpaired MacB proteins create an opening for substrates to enter the pump. Once a substrate binds to an extra MacB, disassociated MacAs can migrate to re-form the complex and expel the substances.

Disrupting the Pump Mechanism

To test whether this mechanism could be interrupted, the researchers devised an ingenious experiment using a microfluidic device developed at UCSF. They applied mechanical stress to deform E. coli cells, disrupting the MacAB-TolC pump and reducing the bacteria’s antibiotic resistance.

This discovery opens new avenues for developing novel antibiotics or enhancing existing ones. By disrupting the efflux pump mechanism, researchers might be able to improve the effectiveness of antibiotics, helping to combat the growing global threat of antibiotic resistance.

A Broader Implication of Protein Stoichiometry

While this study focuses on the MacAB-TolC pump, the findings suggest that protein stoichiometric imbalances may play a functional role in various protein complexes. As Chen points out, “This imbalance of protein stoichiometry must exist for many types of protein complexes. But how does a cell utilize this imbalance?”

The study represents a significant step toward understanding protein complex function and regulation within cells. It underscores the importance of measuring protein concentrations both in the cell as a whole and within specific complexes to uncover their interplay.

Conclusion

By elucidating the mechanisms by which bacteria resist antibiotics, this research represents a vital step forward in the fight against antibiotic resistance. The potential for new clinical interventions is enormous, as researchers can now target the protein complexes responsible for antibiotic expulsion in bacterial cells.

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