An engineered Mycoplasma pneumoniae to fight Staphylococcus aureus

Abstract

Bacterial infections are commonly treated with antimicrobials, but the rise of multi-drug resistance and the presence of biofilms can compromise treatment efficacy. Recently, new approaches using live bacteria or engineered microorganisms have gained attention in the fight against several diseases. In their recent work, Lluch-Senar and colleagues (Garrido et al, 2021) genetically modified the lung pathogen Mycoplasma pneumoniae to attenuate its virulence and secrete antibiofilm and bactericidal enzymes. Their strategy successfully altered a Staphylococcus aureus biofilm on catheters implanted in mice, providing an additional demonstration of the potential of genetically engineered microorganisms as therapeutic agents.

Figure 1. Main steps typically involved in the development of live biotherapeutics products (LBPs)

Once a cell chassis is selected, the first step in LBP development generally consists in performing one or many genetic modifications to ensure the biosafety of the product for its intended usages (left panel). These modifications can, for example, aim at attenuating the virulence of the selected organism or at adding biocontainment measures such as nutritional dependencies. Different validations can be performed to confirm the desired phenotype. In the case of M. pneumoniae, deleting both mpn133 and mpn372 genes (CV2 mutant) resulted in a significant decrease in virulence as shown using a mouse mammary gland infection model, in which the pro‐inflammatory response was also significantly lowered compared with the wild‐type strain (Garrido et al, 2021). The second step of LBP creation involves the addition or programming of therapeutic modules and optimization efforts for cells to properly execute the designed genetic program (middle panel). For example, Lluch‐Senar and colleagues (Garrido et al, 2021) complemented M. pneumoniae with a genetic module allowing the secretion of dispersin B, a glycosyl hydrolase capable of dissolving S. aureus biofilms. With the therapeutic modules loaded into the selected organism, the final step consists of different experiments to evaluate the overall performance of the LBPs (right panel). These experiments usually begin with in vitro assays, followed by more complex investigations using in vivo models. To demonstrate the therapeutic potential of M. pneumoniae secreting dispersin B (CV2‐DispB), Lluch‐Senar and colleagues notably used a mouse model in which catheters containing in vivo‐developed biofilms were treated with subcutaneous injections of M. pneumoniae CV2‐DispB. Following the first round of LBP development, new knowledge emerges and the cell chassis can be further improved, as demonstrated by the addition of the lysostaphin module into M. pneumoniae CV2‐DispB to increase its activity against S. aureus biofilms.