Bacteria vs. bacteria

Bacterial infections are not an area in which one would normally think to try fighting fire with fire, but that’s exactly what a team of researchers is doing in some of the latest efforts against the issue of antibiotic resistance. Recent work headed up by scientists from Imperial College London, the University of Surrey, and the University of Zurich are exploring the potential of targeting resistant strains of bacteria with ones that can out-compete them. Their research, detailed in a paper titled “The loss of the pyoverdine secondary receptor in Pseudomonas aeruginosa results in a fitter strain suitable for population invasion,” was published in The ISME Journal.

“The rapid emergence of antibiotic resistant bacterial pathogens constitutes a critical problem in healthcare and requires the development of novel treatments,” the authors noted in their paper. “Potential strategies include the exploitation of microbial social interactions based on public goods, which are produced at a fitness cost by cooperative microorganisms, but can be exploited by cheaters that do not produce these goods. Cheater invasion has been proposed as a ‘Trojan horse’ approach to infiltrate pathogen populations with strains deploying built-in weaknesses (e.g., sensitiveness to antibiotics). 

“However, previous attempts have been often unsuccessful because population invasion by cheaters was prevented by various mechanisms including the presence of spatial structure (e.g., growth in bio?lms), which limits the diffusion and exploitation of public goods. Here we followed an alternative approach and examined whether the manipulation of public good uptake and not its production could result in potential ‘Trojan horses’ suitable for population invasion.”

The bacteria strain of choice for this work was the sideorophore pyoverdine, which is produced by Pseudomonas aeruginosa MPAO1. According to the CDC, P. aeruginosa is the most common culprit among the Pseudomonas family in terms of infecting humans, leading to infections “in the blood, lungs (pneumonia), or other parts of the body after surgery.” In fact, the CDC notes that “In 2017, multidrug-resistant Pseudomonas aeruginosa caused an estimated 32,600 infections among hospitalized patients and 2,700 estimated deaths in the United States.”

As noted in the paper, “Microorganisms establish communities where social interactions based on cooperation and competition take place.” This can lead bacterial strains to compete with each other, edging out other strains. Often, the most virulent or most evolved strain will come out on top, which is the case seen with antibiotic-resistant bacteria—the bacteria that survive previous antibiotic use develop resistance and survive to become the dominant strain.

As noted in the original Imperial College London press release by Hayley Dunning, Communications and Public Affairs, “P. aeruginosa uses a molecule called pyoverdine to scavenge iron from the environment, then captures this with receptors on the bacteria cell surface. P. aeruginosa has two pyoverdine receptors, which is advantageous when iron is scarce in the environment.”

As the authors reported, however, the second receptor “is detrimental in the presence of an antibacterial stressor and its loss is linked to significant growth advantages.” The team manipulated the bacteria’s uptake by “deleting and/or overexpressing the pyoverdine primary (FpvA) and secondary (FpvB) receptors.” When they generated a strain of P. aeruginosa that lacked FpvB, it was “capable of dominating the wildtype in competition experiments in different scenarios including homogenous cultures, bio?lms and in the colonisation of an animal model” when the strains were exposed to the antibiotic gentamicin.

“We discovered an evolutionary trade-off for these bacteria; one where the cost and benefits of having one or two pyoverdine receptors can be tweaked to our advantage,” explained first author Jaime González of the faculty of Health and Medical Sciences at the University of Surrey. “We also want to investigate other such trade-offs to potentially create a series of Trojan horse candidates for fighting antibiotic-resistant infections.”

As such, future work will consist of testing their new strain against antibiotic-resistant infections and ensuring it can be killed by standard antibiotics and will not develop antibiotic resistance, as per Dunning’s article.

“Antibiotic resistance is rising among many dangerous pathogens, and new methods for tackling these infections are urgently needed. Our approach could provide an alternative to new antibiotics by manipulating the natural tendency of strains of bacteria to compete, allowing us to replace a dangerous strain with one we can treat relatively easily,” said lead researcher Dr. José Jiménez of the Department of Life Sciences at Imperial College London.