Spiramycin Disarms Pseudomonas aeruginosa without Inhibiting Growth
Matteo Calcagnile1, Inès Jeguirim2, Salvatore Maurizio Tredici1
1Department of Biological and Environmental Sciences and Technologies, University of Salento, Via Monteroni, 73100 Lecce, Italy.
Abstract:
Spiramycin is a 16-membered macrolide antibiotic currently used in therapy to treat infections caused by Gram-positive bacteria responsible for respiratory tract infections, and it is also effective against some Gram-negative bacteria and against Toxoplasma spp. In contrast, Pseudomonas aeruginosa, which is one of the pathogens of most concern globally, is intrinsically resistant to spiramycin. In this study we show that spiramycin inhibits the expression of virulence determinants in P. aeruginosa in the absence of any significant effect on bacterial multiplication. In vitro experiments demonstrated that production of pyoverdine and pyocyanin by an environmental strain of P. aeruginosa was markedly reduced in the presence of spiramycin, as were biofilm formation, swarming motility, and rhamnolipid production. Moreover, treatment of P. aeruginosa with spiramycin sensitized the bacterium to H2O2 exposure. The ability of spiramycin to dampen the virulence of the P. aeruginosa strain was confirmed in a Galleria mellonella animal model. The results demonstrated that when G. mellonella larvae were infected with P. aeruginosa, the mortality after 24 h was >90%. In contrast, when the spiramycin was injected together with the bacterium, the mortality dropped to about 50%. Furthermore, marked reduction in transcript levels of the antimicrobial peptides gallerimycin, gloverin and moricin, and lysozyme was found in G. mellonella larvae infected with P. aeruginosa and treated with spiramycin, compared to the larvae infected without spiramycin treatment suggesting an immunomodulatory activity of spiramycin. These results lay the foundation for clinical studies to investigate the possibility of using the spiramycin as an anti-virulence and anti-inflammatory drug for a more effective treatment of P. aeruginosa infections, in combination with other antibiotics.
Insights
Spiramycin, a macrolide antibiotic, reduces virulence factors in Pseudomonas aeruginosa without affecting bacterial growth. This study suggests spiramycin
Area of Science:
- Microbiology
- Pharmacology
- Infectious Diseases
Background:
- Spiramycin is a macrolide antibiotic effective against Gram-positive bacteria and some Gram-negative species, as well as *Toxoplasma* spp.
- *Pseudomonas aeruginosa* is a globally significant pathogen intrinsically resistant to spiramycin.
- Virulence factors of *P. aeruginosa* contribute to its pathogenicity and resistance to treatments.
Purpose of the Study:
- To investigate the effect of spiramycin on the virulence determinants of *Pseudomonas aeruginosa*.
- To evaluate spiramycin's potential as an anti-virulence agent against *P. aeruginosa* infections.
Main Methods:
- In vitro experiments assessing pyoverdine and pyocyanin production, biofilm formation, swarming motility, and rhamnolipid production in *P. aeruginosa* treated with spiramycin.
- Assessment of *P. aeruginosa* sensitivity to hydrogen peroxide (H₂O₂) after spiramycin treatment.
- In vivo study using a *Galleria mellonella* (wax moth larvae) model to evaluate spiramycin's effect on *P. aeruginosa* infection mortality and host immune response.
Main Results:
- Spiramycin significantly inhibited pyoverdine, pyocyanin, biofilm formation, swarming motility, and rhamnolipid production in *P. aeruginosa* without affecting bacterial multiplication.
- Spiramycin treatment sensitized *P. aeruginosa* to H₂O₂.
- In *G. mellonella* model, spiramycin reduced mortality caused by *P. aeruginosa* infection and modulated the expression of antimicrobial peptides and lysozyme, suggesting immunomodulatory effects.
Conclusions:
- Spiramycin exhibits anti-virulence properties against *P. aeruginosa*, inhibiting key virulence factors and increasing susceptibility to oxidative stress.
- Spiramycin demonstrates potential as an immunomodulatory agent in the context of *P. aeruginosa* infection.
- These findings support further clinical investigation of spiramycin as an adjunctive therapy for *P. aeruginosa* infections, potentially in combination with other antibiotics.
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