Bacterial resistance to antibiotics is one of the main global public health threats. According to the World Health Organization (WHO), this silent pandemic causes approximately 700,000 deaths per year and, if the trend is not reversed, it could become the leading cause of mortality by 2050 with 10 million deaths per year.
Now, researchers from the National Center for Biotechnology (CNB), dependent on the Higher Council for Scientific Research (CSIC) in Spain, have publicly presented the results of a study showing how collateral sensitivity can be induced temporarily, something not described until the date, to avoid the appearance of bacterial strains resistant to antibiotics and to improve the therapeutic response of already existing antibacterial drugs.
This is “transient collateral sensitivity”, named after the CNB researchers who authored the study, who are Sara Hernando-Amado, Pablo Laborda and José Luis Martínez. If collateral sensitivity is the evolutionary compensation whereby the acquisition of a resistance mutation to one antibiotic by a bacterium leads to greater sensitivity to another, the type of collateral sensitivity described by the researchers stands out for being temporarily inducible, for prevent the appearance of antibiotic resistance mutations in the treated bacteria and for providing a therapeutic improvement in the use of antibiotics already on the market.
The CNB team led by José Luis Martínez has shown that collateral sensitivity can be induced using dequalinium chloride, a drug with antiseptic and disinfectant properties. This compound, unlike antibiotics, does not select for resistance mutations in different mutant strains and multiresistant clinical strains, but consistently induces transient collateral sensitivity in said strains. In previous studies, the authors identified the appearance of collateral sensitivity to the antibiotic tobramycin after the use of ciprofloxacin, and that this sensitivity was greater when mutations in a specific gene (nfxB) were acquired. On the other hand, the team identified that this compound was capable of temporarily inactivating NfxB, producing transient (inducible) resistance to the antibiotic ciprofloxacin.
Added to this are the results of the present study, in which the researchers show that this transient resistance is also associated with collateral sensitivity to tobramycin. The researcher who has led the work at the CNB, Sara Hernando-Amado, explains that “although the phenomenon of collateral sensitivity has been deeply studied, it had never been considered that it was possible to induce it temporarily, in a non-heritable way, and robust in different mutants and clinical strains resistant to different antibiotics”.
In addition, the researcher continues, “this strategy represents an improvement on the treatment that we recently proposed, where we exploited classic collateral sensitivity, since we induce a higher level of sensitivity to tobramycin. In addition, the resistance caused by dequalinium chloride to ciprofloxacin is transitory, it disappears when this compound does, so that new stable bacterial resistance mutations do not accumulate in the process, as occurs with classical treatments”.
Infection of lung cells by the bacterium Pseudomonas aeruginosa. (Photo: Pablo Laborda (DTU Biosustain))
Sensitivity without resistance
“We wondered if by temporarily inhibiting NfxB activity (thus inducing transient resistance) we could also lead to a state of transient sensitivity to tobramycin, something that we could exploit therapeutically and that would prevent the selection of mutants resistant to a first antibiotic. ”, explains Hernando-Amado.
The results of José Luis Martínez’s group show that the combined use of dequalinium chloride and tobramycin eliminates both resistant mutant strains of the Pseudomonas aeruginosa bacterium (a prevalent pathogen that causes infections in hospitalized patients or those with previous pathologies and that generates chronic infections in patients with cystic fibrosis) as highly varied clinical strains, including those initially resistant to tobramycin, and without causing the acquisition of genetic mutations that favor resistance to other antibiotics.
This work shows that the use of this compound and others yet to be identified could allow the design of new therapeutic strategies to treat bacterial infections.
The study is titled “Tackling antibiotic resistance by inducing transient and robust collateral sensitivity”. And it has been published in the academic journal Nature Communications. (Source: Susana de Lucas / CNB / Alejandro Parrilla / CSIC)