Mechanism for antibiotic resistance in Pseudomonas explained in new research

By Dr. Ananya Mandal, MDOct 30 2019

A new study has revealed the underlying mechanism of development of antibiotic resistance among Pseudomonas aeruginosa (P. aeruginosa). Pseudomonas is known to cause severe and often life threatening infections in humans. These infections become further difficult to treat because of the development of resistance against commonly used antibiotics.

The results of the study titled, “Evolutionary stability of collateral sensitivity to antibiotics in the model pathogen Pseudomonas aeruginosa,” in the latest issue of the journal eLife.

Bacterium Pseudomonas aeruginosa. Illustration shows polar location of flagella and presence of pili on the bacterial surface. Image Credit: Kateryna Kon / Shutterstock

Pseudomonas infections have been a menace and many of these infections are nosocomial. This means that these infections are often caught in the hospital or healthcare setting. At present another emerging problem is emergence of multidrug-resistant Pseudomonas strains that are difficult to treat with the commonly used antibiotics. This new study provides an understanding of the antibiotic resistance developed by these organisms and may help treat resistant strains of the infection and develop antibiotics suitable against these strains.

First author of the study, Camilo Barbosa, working as a postdoctoral student in senior author Hinrich Schulenburg's lab at the Kiel Evolution Center (KEC) of Kiel University, Germany, spoke about this study. He said, “Antibiotic resistance is one of the most serious threats to public health worldwide. The World Health Organization warns of a post-antibiotic era in which infections can no longer be treated and could become one of the most frequent non-natural causes of death.” He added, “The rapid evolution of antibiotic resistance makes antibacterial drugs ineffective within short periods of time, which means we need new strategies to maintain or even improve the effectiveness of existing antibiotics. But this development needs to take the relevant evolutionary processes into account, or else new drugs will likely fail.”

Speaking about the emergency of resistant strains, the team wrote, “Evolution is at the core of the impending antibiotic crisis. Sustainable therapy must thus account for the adaptive potential of pathogens.”

The team in this study looked at something called “collateral sensitivity” in the Pseudomonas species of bacteria. Collateral sensitivity is seen when the bacteria develop resistance to one of the antibiotics but in turn become highly sensitive to another antibiotic. This means that when one of the antibiotics fails to work, another tends to work well in killing the organism. The team called development of collateral sensitivity a “trade off” in developing antibiotic resistance. They wrote, “To date, the evolutionary stability and thus clinical utility of this trade-off is unclear.” Evolutionary stability refers to the stabilization of a strain of bacteria that has developed a mutation which makes it drug resistant.

Barbosa explained, “While a variety of distinct cases of collateral sensitivities have previously been described, it was still unclear whether they could be exploited for antibiotic treatment. We tested one key requirement of this principle for medical implementation: stability of the evolutionary trade-off. Is collateral sensitivity stable across time, thereby allowing us to exploit it as a trade-off in order to eliminate bacterial populations and/or prevent emergence of drug resistance?”

The team exposed the Pseudomonas strains to different drugs and found that it showed evolved collateral sensitivity against several drugs. Some of these strains that develop collateral sensitivity remain stable and can prevent the development of multidrug resistance the authors of the study wrote. The development of the collateral sensitivity also depended upon the order in which the different drugs were used the team explained. Barbosa said, “The pathogen's ability to adapt was particularly constrained when the treatment included a drug change from an aminoglycoside to a beta-lactam, a penicillin-like substance.” He said that there were underlying genetic mechanisms at play in this development of collateral sensitivity. He added that when the bacteria did not develop collateral sensitivity and adapt to the sequential use of the antibiotics, the strains died out and became extinct.

The authors write that there were three main outcomes identified from this study including;

• bacteria commonly failed to counter hypersensitivity and went extinct
• hypersensitivity sometimes converted into multidrug resistance; and
• resistance gains frequently caused re-sensitization to the previous drug, thereby maintaining the trade-off.

Senior member of the team Hinrich Schulenburg, Professor in Zoology at the KEC said in his statement, “The effects of changing certain drug classes and the impact of evolutionary costs on the development of resistance demonstrate the enormous potential of evolutionary principles for the design of new, sustainable antibiotic therapies. As a next step, we plan to further develop these promising evolution-based strategies so that they may one day be used in patient treatment.”