Lab-Designed Molecules Offer New Approach to Treating Superbug Infections

A scientific team including researchers from the Spanish National Research Council (CSIC) says it has made a significant advance against superbugs and their resistance to multiple drugs. The group designed molecules that can disrupt the cellular mechanisms that lead these bacteria to becoming unaffected by conventional antibiotics. The study (“Membrane Microdomain Disassembly Inhibits MRSA Antibiotic Resistance”) appears in Cell.

“A number of bacterial cell processes are confined functional membrane microdomains (FMMs), structurally and functionally similar to lipid rafts of eukaryotic cells. How bacteria organize these intricate platforms and what their biological significance is remain important questions. Using the pathogen methicillin-resistant Staphylococcus aureus (MRSA), we show here that membrane-carotenoid interaction with the scaffold protein flotillin leads to FMM formation, which can be visualized using super-resolution array tomography,” write the investigators.

“These membrane platforms accumulate multimeric protein complexes, for which flotillin facilitates efficient oligomerization. One of these proteins is PBP2a, responsible for penicillin resistance in MRSA. Flotillin mutants are defective in PBP2a oligomerization. Perturbation of FMM assembly using available drugs interferes with PBP2a oligomerization and disables MRSA penicillin resistance in vitro and in vivo [mice], resulting in MRSA infections that are susceptible to penicillin treatment. Our study demonstrates that bacteria possess sophisticated cell organization programs and defines alternative therapies to fight multidrug-resistant pathogens using conventional antibiotics.”

The work focused on directly attacking those areas of the bacteria where the proteins assemble to form complexes. “These microdomains in the cell membrane—called lipid rafts—are crucial because they form many protein complexes related to resistance to antibiotics,” says Daniel López, Ph.D., a researcher at CSIC's National Centre for Biotechnology.

To date, bacteria had not been shown to have the complex cellular organization based on the assembly platforms that are present in eukaryotic cells. In these areas of the cell membrane, the proteins responsible for forming large complexes do so efficiently. “If they are confined to these tiny farms, the formation of molecular complexes important for the physiology of the bacteria is successfully achieved,” adds Dr. López.

After characterization of the bacterium's proteins and lipids using advanced techniques such as cryotomography, the researchers chose a group of molecules capable of disassembling the lipid rafts. Many of these molecules are the same as those prescribed, in certain cases, to treat high cholesterol.

“Since we know that many of the proteins related to antibiotic resistance are assembled in these microdomains, what we have done is to generate a strategy to break them down and to attempt to eliminate their resistance. The molecules we have designed make all these proteins stop working and become disorganized. In short, they succeed in making a resistant bacteria stop being resistant,” points out Dr. López.

The researchers suggest using these molecules in combination with methicillin in the treatment of invasive infections by superbugs. As Dr. López explains, “First, resistance would be disassembled before aiming a direct attack on the bacteria with a common antibiotic. It's interesting because the option now becomes open to us to combat superbugs using an entirely new approach.”

And if the bacteria were to mutate once again, building resistance to this new treatment? Dr. López replies that the chances of that happening are remote since eliminating the lipid rafts “takes away biological pressure on the bacteria to change. That is, it does not affect their survival and, therefore, they do not undergo the changes that would generate resistance”.