Up Close and Personal with a "Last Resort" Antibiotic!

As we all know, antibiotics can be finicky, to say the least. Many bacteria have become resistant to them, leading to serious infection cases wherein the patients have no choice but to undergo treatment via "last resort" antibiotics. Sure, they'll probably kill the bacteria causing the infection, but they aren't much nicer to your own cells. An article I found to be extremely interesting detailed the results of research into one of these last resort antibiotics, which had a surprising and potentially enlightening mechanism of operation.

For almost 90 years, Polymyxin B has been one of the final options physicians turn to when treating dangerous gram negative infections. It is often described as a simple membrane disrupting drug one that punches through the protective layers of a bacterial cell until the cell collapses. But recent work done in a study by researchers in London has revealed that its activity is far more dependent on the state of the bacterium than we once realized. The study shows that Polymyxin B does not act the same way on all cells and that the antibiotic needs the bacterium to be energetically awake in order to deliver its full lethal effect.

The central finding of the research is that Polymyxin B requires an actively respiring bacterial cell in order to breach the outer membrane. When bacteria have access to a carbon source and are running normal metabolic processes, the drug can trigger dramatic changes in the outer membrane. The membrane begins to bulge outward and lose sections of its lipopolysaccharide layer, which is normally one of the most important protective barriers of a gram negative cell. Once this barrier is weakened, the drug then gains access to the inner membrane where it can cause rapid collapse of the cell.

The effect of Polymyxin B on a bacterium

In contrast, however, the same antibiotic does far less damage when the cell is in a low energy state. Dormant bacteria or bacteria that have been starved of nutrients do not provide the same environment for Polymyxin B to exert its action. Without strong metabolic activity, the outer membrane remains stable and does not undergo the structural changes that allow the antibiotic to break through. As a result these metabolically quiet cells survive exposure even at concentrations that would normally be lethal.

Even according to the researchers themselves, this creates an important shift in how we think about membrane targeting antibiotics. Instead of acting purely from the outside inward, Polymyxin B relies on the bacterium’s own metabolic processes to weaken its defenses. The drug is not simply dissolving the membrane. It is exploiting the stresses the cell places on itself when it is actively growing. This may explain why certain persistent types of bacterial infections are so hard to eliminate; their low metabolic state unintentionally protects them.

The clinical implications of this discovery are potentially significant. If the effectiveness of Polymyxin B depends on bacterial activity, then future gram-negative antibiotic treatments, Polymyxin related or not, may find greater success by accounting for the energy state of the infection. It raises the possibility that pairing the drug with compounds that stimulate metabolism or wake dormant cells could improve outcomes. It also warns that standard laboratory tests may underestimate how differently the antibiotic behaves in living infections compared with simple broth cultures.

The two different bacterial cell walls

Ultimately this research highlights how even long established antibiotics can still surprise us. Polymyxin B is not simply a brute force membrane destroyer. Its success depends on a partnership between the drug and the metabolism of the bacterium itself. Understanding that partnership more deeply may help us design better therapies and revive the usefulness of drugs that we once thought we fully understood.