False targets for an antibiotic

Staphylococci were protected from the last reserve antibiotic by "false targets"

Oleg Lischuk, N+1

British researchers have discovered that drug-resistant Staphylococcus aureus inactivates the last reserve antibiotic daptomycin, throwing out "false targets" from membrane phospholipids. Moreover, their action is facilitated by a mutation that is often observed in nosocomial strains of the bacterium. The results of the work are published in the journal Nature Microbiology (Pader et al., Staphylococcus aureus inactivates daptomycin by releasing membrane phospholipids).

Daptomycin is a relatively new antibiotic isolated in the 1980s from a culture of soil bacteria Streptomyces roseosporus. It is effective against most gram-positive bacteria resistant to other groups of antibiotics, due to an unusual mechanism of action. Upon contact with a bacterial cell, this lipopeptide is embedded in its membrane, changing its characteristics and increasing its permeability to ions, which disrupts the main processes of the microorganism's vital activity and leads to its death. Nevertheless, cases of resistance to daptomycin have been registered since 2005, and currently the ineffectiveness of therapy for them reaches 20 percent of cases. Moreover, nosocomial strains of staphylococcus are much more likely to show antibiotic resistance than natural ones. The mechanism of such stability has not yet been known.

The staff of Imperial College London conducted a series of experiments with various strains of Staphylococcus aureus. They were convinced that, as previously shown, daptomycin has a much worse effect on hospital strains of bacteria, which often have a defect in the Agr forum sense system (this system allows some types of bacteria to coordinate their collective actions by developing chemical stimuli).

By placing bacteria and their waste products in various conditions, scientists found out that the inactivation of the antibiotic is due to the fact that staphylococci actively secrete "false targets" into the environment in the form of individual molecules and small micelles of phosphatidylglycerin (PH) of their membranes (the main target of daptomycin). At the same time, although PH is isolated by all strains of the pathogen, it effectively binds the antibiotic only in bacteria with an Agr defect.

Analyses of culture fluids have shown that in the absence of an Agr defect, one of the groups of signaling molecules of this system (phenol-soluble alpha modulins) released into the medium binds to PH, preventing its interaction with daptomycin. In mutant strains with impaired synthesis of phenol-soluble alpha modulins, the isolated PH remained in free form and effectively neutralized the antibiotic.

Taking into account the available data that the antibiotic oxacillin (a derivative of penicillin) acting on the cell wall enhances the effect of daptomycin, scientists investigated their combined effect on different strains of staphylococcus. It turned out that oxacillin in doses lower than therapeutic ones restores the activity of daptomycin against bacteria with an Agr defect, since it reduces the level of PH release. In natural strains, this effect was not observed, presumably because their phenol-soluble alpha modulins themselves were sufficient to neutralize PH.

Thus, the researchers not only explained the mechanism of staphylococcus resistance to daptomycin, but also identified a way to restore the effectiveness of the antibiotic.

Recently, resistance to antibiotics, including the most powerful and having a wide spectrum of action, has become a global problem and one of the main threats to public health. Emerging new resistance genes are easily transmitted between different species and even genera of bacteria. Striking examples of such genes are NDM-1, which provides resistance to beta-lactam antibiotics (penicillins, cephalosporins and carbapenems), and MCR-1, which is responsible for the inefficiency of polymyxins. Because of this, the problem of antibiotic resistance was discussed this year at the UN General Assembly and became only the fourth health issue discussed at this level in the history of the organization.

Recently, American and Israeli scientists conducted an interesting experiment that made it possible to directly observe the emergence and evolution of "super-microbes" with multidrug resistance.

Portal "Eternal youth" http://vechnayamolodost.ru  25.10.2016